Heterocycles as potassium channel modulators

ABSTRACT

Compounds, compositions and methods are provided which are useful in the treatment of diseases through the modulation of potassium ion flux through voltage-dependent potassium channels. More particularly, the invention provides heterocycles, compositions and methods that are useful in the treatment of central or peripheral nervous system disorders (e.g., migraine, ataxia, Parkinson&#39;s disease, bipolar disorders, trigeminal neuralgia, spasticity, mood disorders, brain tumors, psychotic disorders, myokymia, seizures, epilepsy, seizure, retinal degeneration, hearing and vision loss, Alzheimer&#39;s disease, age-related memory loss, learning deficiencies, anxiety, neuronal degeneration and motor neuron diseases, maintaining bladder control or treating urinary incontinence) and as neuroprotective agents (e.g., to prevent stroke and the like) by modulating potassium channels associated with the onset or recurrence of the indicated conditions.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 60/956,640 filed Aug. 17, 2007 and U.S. Provisional PatentApplication No. 61/078,241 filed Jul. 3, 2008, which applications areincorporated herein by reference in its entirety and for all purposes.

BACKGROUND OF THE INVENTION

Ion channels are cellular proteins that regulate the flow of ions,including calcium, potassium, sodium and chloride, into and out ofcells. These channels are present in all human cells and affect suchprocesses as nerve transmission, muscle contraction and cellularsecretion. Among the ion channels, potassium channels are the mostubiquitous and diverse, being found in a variety of animal cells such asnervous, muscular, glandular, immune, reproductive, and epithelialtissue. These channels allow the flow of potassium in and/or out of thecell under certain conditions. For example, the outward flow ofpotassium ions upon opening of these channels makes the interior of thecell more negative, counteracting depolarizing voltages applied to thecell. These channels are regulated, e.g., by calcium sensitivity,voltage-gating, second messengers, extracellular ligands, andATP-sensitivity.

Potassium channels are associated with a number of physiologicalprocesses, including regulation of heartbeat, dilation of arteries,release of insulin, excitability of nerve cells, and regulation of renalelectrolyte transport. Potassium channels are made by alpha subunitsthat fall into at least 8 families, based on predicted structural andfunctional similarities (Wei et al, Neuropharmacology 35(7): 805-829(1997)). Three of these families (Kv, eag-related, and KQT) share acommon motif of six transmembrane domains and are primarily gated byvoltage. Two other families, CNG and SK/IK, also contain this motif butare gated by cyclic nucleotides and calcium, respectively. The threeother families of potassium channel alpha subunits have distinctpatterns of transmembrane domains. Slo family potassium channels, or BKchannels have seven transmembrane domains (Meera et al., Proc. Natl.Acad. Sci. U.S.A. 94(25): 14066-71 (1997)) and are gated by both voltageand calcium or pH (Schreiber et al., J. Biol. Chem. 273: 3509-16(1998)). Another family, the inward rectifier potassium channels (Kir),belongs to a structural family containing two transmembrane domains, andan eighth functionally diverse family (TP, or “two-pore”) contains twotandem repeats of this inward rectifier motif.

Potassium channels are typically formed by four alpha subunits, and canbe homomeric (made of identical alpha subunits) or heteromeric (made oftwo or more distinct types of alpha subunits). In addition, potassiumchannels made from Kv, KQT and Slo or BK subunits have often been foundto contain additional, structurally distinct auxiliary, or beta,subunits. These subunits do not form potassium channels themselves, butinstead they act as auxiliary subunits to modify the functionalproperties of channels formed by alpha subunits. For example, the Kvbeta subunits are cytoplasmic and are known to increase the surfaceexpression of Kv channels and/or modify inactivation kinetics of thechannel (Heinemann et al., J. Physiol. 493: 625-633 (1996); Shi et al.,Neuron 16(4): 843-852 (1996)). In another example, the KQT family betasubunit, minK, primarily changes activation kinetics (Sanguinetti etal., Nature 384: 80-83 (1996)).

Slo or BK potassium channels are large conductance potassium channelsfound in a wide variety of tissues, both in the central nervous systemand periphery. They play a key role in the regulation of processes suchas neuronal integration, muscular contraction and hormone secretion.They may also be involved in processes such as lymphocytedifferentiation and cell proliferation, spermatocyte differentiation andsperm motility. Three alpha subunits of the Slo family have been cloned,i.e., Slo1, Slo2, and Slo3 (Butler et al., Science 261: 221-224 (1993);Schreiber et al., J. Biol. Chem., 273: 3509-16 (1998); and Joiner etal., Nature Neurosci. 1: 462-469 (1998)). These Slo family members havebeen shown to be voltage and/or calcium gated, and/or regulated byintracellular pH.

Certain members of the Kv family of potassium channels were recentlyrenamed (see, Biervert, et al., Science 279: 403-406 (1998)). KvLQT1 wasre-named KCNQ1, and the KvLQT1-related channels (KvLR1 and KvLR2) wererenamed KCNQ2 and KCNQ3, respectively. More recently, additional membersof the KCNQ subfamily were identified. For example, KCNQ4 was identifiedas a channel expressed in sensory outer hair cells (Kubisch, et al.,Cell 96(3): 437-446 (1999)). KCNQ5 (Kananura et al., Neuroreport11(9):2063 (2000)), KCNQ 2/3 (Main et al., Mol. Pharmacol. 58: 253-62(2000), KCNQ 3/5 (Wickenden et al., Br. J. Pharma 132: 381 (2001)) andKCNQ6 have also recently been described.

KCNQ2 and KCNQ3 have been shown to be nervous system-specific potassiumchannels associated with benign familial neonatal convulsions (“BFNC”),a class of idiopathic generalized epilepsy (see, Leppert, et al., Nature337: 647-648 (1989)). These channels have been linked to M-currentchannels (see, Wang, et al., Science 282: 1890-1893 (1998)). Thediscovery and characterization of these channels and currents providesuseful insights into how these voltage dependent (Kv) potassium channelsfunction in different environments, and how they respond to variousactivation mechanisms. Such information has now led to theidentification of modulators of KCNQ2 and KCNQ3 potassium channels orthe M-current, and the use of such modulators as therapeutic agents.

SUMMARY OF THE INVENTION

This invention relates to the use of certain heterocycles as potassiumchannel modulators and to the treatment of diseases in which a potassiumchannel is implicated. Additionally, this invention relates to novelcompounds that are useful as potassium channel modulators. Inparticular, the present invention provides heterocycles andpharmaceutically acceptable salts, hydrates or solvates thereof, whichare useful in the treatment of diseases through the modulation ofpotassium ion flux through voltage-dependent potassium channels.

In one aspect, the present invention provides a compound of Formula (I):

or a pharmaceutically acceptable salt, solvate or complex thereof,wherein Q, W, Z are members independently selected from carbon andnitrogen; with the proviso that when Q is nitrogen, W and Z are carbon;with the further proviso that when W is nitrogen, Q and Z are carbon;with the further proviso that when Z is nitrogen, Q and W are carbon. Xis a member selected from carbon and nitrogen. Y is a member selectedfrom —(CH₂)_(n)—C(O)—NR⁵—, —(CH₂)_(n)—NR⁵—C(O)—,—(CH₂)_(n)—CR⁶R⁷NR⁵C(O)—, —(CH₂)_(n)—S(O)₂—NR⁵— and—(CH₂)_(n)—NR⁵—S(O)₂—. The index n is an integer selected from 0, 1, 2,3, 4, 5 and 6. R⁵, R⁶ and R⁷ are members independently selected from H,substituted or unsubstituted C₁-C₇ alkyl group, substituted orunsubstituted aryl and substituted or unsubstituted arylalkyl. R¹ and R²are members independently selected from H, C₁-C₇ substituted orunsubstituted alkyl, CN, CF₃, OCF₃, SCF₃, halogen, thioalkyl, S(O)R⁸,S(O)₂R⁸, C(O)R⁸, C(O)₂R⁸, substituted or unsubstituted benzyl,substituted or unsubstituted phenyl and substituted or unsubstitutedheteroaryl. R⁸ is a member selected from H, substituted or unsubstitutedC₁-C₇ alkyl, substituted or unsubstituted benzyl, substituted orunsubstituted phenyl and substituted or unsubstituted heteroaryl. R³ isa member selected from the group consisting of CF₃, —(CH₂)_(m)CF₃,substituted or unsubstituted C₁-C₉ alkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl and substituted orunsubstituted C₃-C₈ cycloalkyl. The index m is an integer selected from0, 1, 2, 3, 4, 5 and 6. R⁴ is a member selected from substituted orunsubstituted C₁-C₉ alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cyclo or bicyclo alkyl and —(CH₂)_(p)CF₃. The index p is aninteger selected from 0, 1, 2, 3, 4, 5 and 6.

In another aspect, the present invention provides a compound of Formula(V)

or a pharmaceutically acceptable salt, hydrate, solvate or complexthereof, wherein: X is Nitrogen; Y is a member selected from the group—(CH₂)n-C(O)—NR₅—, —(CH₂)n-NR₅—C(O)—, —(CH₂)n—CR₆R₇NR₅C(O)—,—(CH₂)n-S(O)₂—NR₅—, —(CH₂)n-NR₅—S(O)₂—; wherein R₅, R₆ and R₇ are amember selected from —H, substituted or unsubstituted C₁-C₇ alkyl groupand n is an integer from 0-6, substituted or unsubstituted aryl,substituted or unsubstituted alkyl aryl; R₁ and R₂ are independently —H,C₁-C₇ substituted or unsubstituted alkyl, CN, CF₃, OCF₃, SCF₃, halogen,thioalkyl, S(O)R₈ S(O)₂R₈, C(O)R₈, C(O)₂R₈, optimally substitutedbenzyl, phenyl or heteroaryl; wherein R₈ is a member selected from thegroup consisting of —H and a substituted or unsubstituted C₁-C₇ alkyl,optimally substituted benzyl, phenyl or heteroaryl; group; R₃ is amember selected from the group consisting of CF₃, —(CH₂)nCF₃, wherein nis an integer from 0-6, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl; R⁴ is amember selected from the group consisting of substituted orunsubstituted C₁-C₉ alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₉ cyclo or bicyclo alkyl, or —(CH₂)nCF₃, wherein n is an integerfrom 0-6.

In yet another aspect, the present invention provides a compound ofFormula (IX):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,R¹¹ and R¹² are each independently selected from the group consisting of—H, halogen, C₁₋₈haloalkyl, —CN, C₁₋₈alkyl, C₁₋₈alkoxy, aryloxy andaryl-C₁₋₈alkoxy;R¹³ is selected from the group consisting of —H, C₁₋₈alkyl, C₂₋₈alkenyl,aryl, C₃₋₈cycloalkyl, aryl-C₁₋₆alkyl, C₃₋₈cycloalkyl-C₁₋₈alkyl,heteroaryl and heteroaryl-C₁₋₆alkyl, wherein the aromatic portion of theR¹³ group is optionally substituted with from 1-3 R^(a) substituents,each R^(a) is independently selected from the group consisting ofhalogen, C₁₋₈haloalkoxy, C₁₋₈alkoxy, C₁₋₈haloalkyl, —CN and R^(b),wherein R^(b) is C₁₋₈alkyl optionally substituted with from 1-2substituents selected from halogen, —CN, —OH, C₁₋₈haloalkoxy orC₁₋₈alkoxy; or any two adjacent R^(a) substituents together with theatoms to which they are attached form a 5- or 6-membered carbocyclicring, optionally substituted with a C₁₋₈alkyl;R¹⁴ is selected from the group consisting of C₁₋₈alkyl, C₁₋₈haloalkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₈alkyl, aryl, aryl-C₁₋₈alkyl,C₁₋₈alkoxy, aryl-C₁₋₈alkoxy, C₄₋₅heterocycloalkyl,C₄₋₅heterocycloalkyl-C₁₋₈alkyl, R^(c), —NHR^(d) and —N(R^(d))₂, whereinR^(c) is C₁₋₈alkyl substituted with from 1-2 members selected from —OH,—CH₂N(R^(d))₂, —OC(O)C₁₋₈alkyl, —OC(O)aryl, C₁₋₈alkoxy or aryloxy andR^(d) is C₁₋₈alkyl or aryl-C₁₋₈alkyl, wherein the aromatic portion ofthe R¹⁴ group is optionally substituted with from 1-3 R^(e) substituentsindependently selected from the group consisting of halogen,C₁₋₈haloalkyl, C₁₋₈alkyl, C₁₋₈alkoxy, —CN or haloalkoxy, —OH,—OC(O)O—R^(f), —OC(O)R^(f), —OC(O)NHR^(f), —OC(O)N(R^(f))₂, —S(O)R^(f);—S(O)₂R^(f), —SO₂NH₂, —S(O)₂NHR^(f), —S(O)₂N(R^(f))₂, —NHS(O)₂R^(f),—NR^(f)S(O)₂R^(f), —C(O)NH₂, —C(O)NHR^(f), —C(O)N(R^(f))₂, —C(O)R^(f);—C(O)H, wherein each R^(f) is independently a C₁₋₈alkyl; and thecycloalkyl portion of the R¹⁴ group is optionally substituted with from1-3 substituents selected from halogen, C₁₋₈alkyl or optionally fusedwith a 5- or 6-membered aromatic ring having from 0-2 heteroatoms asring members selected from N, O or S; R¹⁵ is —H or —C(O)C₁₋₈alkyl;Z¹ is ═N— or ═C(R¹⁶)— and Z² is ═N— or ═C(R¹⁷)—, wherein R¹⁶ and R¹⁷ areeach independently —H, C₁₋₈alkyl, halogen, —CN, C₁₋₈haloalkyl,C₁₋₈haloalkoxy, —OR^(g) or —N(R^(g))₂, wherein R^(g) is independently—H, C₁₋₈alkyl or aryl-C₁₋₈alkyl, with the proviso that Z¹ and Z² are notsimultaneously ═N—;In Formula (IX), at each occurrence, “alkyl” by itself or as part ofanother substituent, is an unsubstituted, fully saturated, straight orbranched chain hydrocarbon radical unless specified otherwise;In Formula (IX), at each occurrence, “cycloalkyl” by itself or as partof another substituent is an unsubstituted, fully saturated, cyclichydrocarbon radical unless specified otherwise; andIn Formula (IX), at each occurrence, “aryl” by itself or as part ofanother substituent is a monovalent monocyclic, bicyclic or polycyclicpolyunsaturated aromatic hydrocarbon radical. In some preferredembodiments, “aryl” by itself or as part of another substituent denotesa monovalent monocyclic, bicyclic or polycyclic polyunsaturatedunsubstituted aromatic hydrocarbon radical unless otherwise specifiedand “heteroaryl” by itself or as part of another substituent denotesunsubstituted aryl groups (or rings) that contains from one to fiveheteroatoms selected from N, O, or S, wherein the nitrogen and sulfuratoms are optionally oxidized, and the nitrogen atom(s) are optionallyquaternized unless otherwise specified.

In still another aspect, the present invention provides a method forincreasing flow through voltage dependent potassium channels in a cell.The method includes contacting the cell with a compound as describedherein. In some embodiments, the method includes contacting the cellwith a compound of Formula I, V or IX in an amount sufficient to openthe potassium channels.

In yet another aspect, the present invention provides a method fortreating a central or peripheral nervous system disorder or conditionthrough the modulation of a voltage-dependent potassium channel. Themethod includes administering to a subject in need of such treatment aneffective amount of a compound of as described herein. In someembodiments, the method includes administering to a subject in need ofsuch treatment an effective amount of a compound of Formula I, V or IX.

Other objects and advantages of the present invention will be apparentfrom the detailed description that follows.

DETAILED DESCRIPTION OF THE INVENTION AND THE PREFERRED EMBODIMENTSAbbreviations and Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. For example: CHO, Chinese hamster ovary;EBSS, Earl's Balanced Salt Solution; KCNQ, potassium channel Q; KCNQ2,potassium channel Q2, hSK, Ca²⁺ activated small conductance potassiumchannels; SDS, sodium dodecyl sulfate; Et₃N, triethylamine; MeOH,methanol; and DMSO, dimethylsulfoxide; DCM, dichloromethane; NBS,N-bromosuccinimide; NIS, N-iodosuccinimide; TsCl, toluenesulfonylchloride, dppa, diphenylphosphonic azide; TFAA, trifluoro acetic acid;THF, tetrahydrofuran.

The term “pain” refers to all categories of pain, including pain that isdescribed in terms of stimulus or nerve response, e.g., somatic pain(normal nerve response to a noxious stimulus) and neuropathic pain(abnormal response of a injured or altered sensory pathway, oftenwithout clear noxious input); pain that is categorized temporally, e.g.,chronic pain and acute pain; pain that is categorized in terms of itsseverity, e.g., mild, moderate, or severe; and pain that is a symptom ora result of a disease state or syndrome, e.g., inflammatory pain, cancerpain, AIDS pain, arthropathy, migraine, trigeminal neuralgia, cardiacischaemia, and diabetic neuropathy (see, e.g., Harrison's Principles ofInternal Medicine, pp. 93-98 (Wilson et al., eds., 12th ed. 1991);Williams et al., J. of Med. Chem. 42: 1481-1485 (1999), herein eachincorporated by reference in their entirety).

“Somatic” pain, as described above, refers to a normal nerve response toa noxious stimulus such as injury or illness, e.g., trauma, burn,infection, inflammation, or disease process such as cancer, and includesboth cutaneous pain (e.g., skin, muscle or joint derived) and visceralpain (e.g., organ derived).

“Neuropathic” pain, as described above, refers to pain resulting frominjury to or chronic changes in peripheral and/or central sensorypathways, where the pain often occurs or persists without an obviousnoxious input.

“Acute pain”, as described above, refers to pain which is marked byshort duration or a sudden onset.

“Chronic pain”, as described above, refers to pain which is marked bylong duration or frequent recurrence.

“Inflammatory pain”, as described above, refers to pain which isproduced as a symptom or a result of inflammation or an immune systemdisorder.

“Visceral pain”, as described above, refers to pain which is located inan internal organ.

“Biological medium,” as used herein refers to both in vitro and in vivobiological milieus. Exemplary in vitro “biological media” include, butare not limited to, cell culture, tissue culture, homogenates, plasmaand blood. In vivo applications are generally performed in mammals,preferably humans.

“Compound of the invention,” as used herein refers to a compounddescribed herein, pharmaceutically acceptable salts, hydrates orsolvates thereof, e.g., compounds of Formulas I, II, III, IV, V, VI,VII, VIII, IX, IXa, IXa-1, IXa-2, IXa-3, IXa-4, IXa-5, IXa-6, IXa-7,IXb-1, IXb-2, IXb-3, IXb-3, IXb-4, IXb-5, IXc, IXc-1 and IXc-2.

“Modulating,” as used herein, refers to the ability of a compound of theinvention to activate and/or inhibit a potassium channel, preferably, aKCNQ potassium channel. In some preferred embodiments, a compound of theinvention activates a potassium channel, preferably, a KCNQ potassiumchannel.

“Opening” and “activating” are used interchangeably herein to refer tothe partial or full activation of a KCNQ channel by a compound of theinvention, which leads to an increase in ion flux either into or out ofa cell in which a KCNQ channel is found.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents which would result from writing thestructure from right to left, e.g., —CH₂O— is intended to also recite—OCH₂—; —NHS(O)₂— is also intended to represent. —S(O)₂HN—, etc.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight- or branched-chain, or cyclichydrocarbon radical, or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di- andmultivalent radicals, having the number of carbon atoms designated (i.e.C₁₋₈ or C₁-C₈ means one to ten carbons). Examples of saturatedhydrocarbon radicals include, but are not limited to, groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologsand isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, andthe like. An unsaturated alkyl group is one having one or more doublebonds or triple bonds. Examples of unsaturated alkyl groups include, butare not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl,2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and3-propynyl, 3-butynyl, and the higher homologs and isomers. The term“alkyl,” unless otherwise noted, also preferably include thosederivatives of alkyl defined in more detail below, such as“heteroalkyl.” Alkyl groups that are limited to hydrocarbon groups aretermed “homoalkyl”. The term “alkyl”, as used herein refers to alkyl,alkenyl and alkynyl moieties, each of which can be mono-, di- orpolyvalent species. Alkyl groups are preferably substituted, e.g., withone or more group referred to herein below as an “alkyl groupsubstituent.” In one embodiment, alkyl includes a straight or branchedchain fully saturated aliphatic hydrocarbon radicals having the numberof carbon atoms designated. For example, C₁₋₈alkyl refers to ahydrocarbon radical straight or branched having 1, 2, 3, 4, 5, 6, 7 or 8carbon atoms and includes, but are not limited to, C₁₋₂alkyl, C₁₋₄alkyl, C₂₋₆ alkyl, C₂₋₄ alkyl, C₁₋₆ alkyl, C₂₋₈alkyl, C₁₋₇alkyl,C₂₋₇alkyl and C₃₋₈ alkyl. In some preferred embodiments, at eachoccurrence, “alkyl” is by itself or as part of another substituent, isan unsubstituted, fully saturated, straight or branched chainhydrocarbon radical unless otherwise specified.

The term “alkenyl” by itself or as part of another substituent refers toa linear or branched monovalent hydrocarbon radical, which may be mono-or polyunsaturated, having the number of carbon atoms designated. Forexample, “C₂₋₈ alkenyl” means an alkenyl radical having from 2, 3, 4, 5,6, 7 or 8 atoms that is derived by the removal of one hydrogen atom froma single carbon atom of a parent alkane. Examples include, but are notlimited to vinyl, 2-propenyl i.e. —CH═C(H)(CH₃), —CH═C(CH₃)₂,—C(CH₃)═C(H)₂, —C(CH₃)═C(H)(CH₃), —C(CH₂CH₃)═CH₂, butadienyl e.g.2-(butadienyl), pentadienyl e.g. 2,4-pentadienyl and3-(1,4-pentadienyl), and hexadienyl, among others, and higher homologsand stereoisomers thereof.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified, but notlimited, by —CH₂CH₂CH₂CH₂—, and further includes those groups describedbelow as “heteroalkylene.” Typically, an alkyl (or alkylene) group willhave from 1 to 24 carbon atoms, with those groups having 10 or fewercarbon atoms being preferred in the present invention. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms. In some preferredembodiments, “alkylene” by itself or as part of another substituentmeans a linear or branched saturated divalent unsubstituted hydrocarbonradical unless specified otherwise. For example, C₁₋₆alkylene is meantto include methylene, ethylene, propylene, 2-methylpropylene, pentylene,and the like.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcyclic hydrocarbon radical, or combinations thereof, consisting of thestated number of carbon atoms and at least one heteroatom selected fromthe group consisting of O, N, Si and S, and wherein the nitrogen andsulfur atoms may optionally be oxidized and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) O, N and S and Si may beplaced at any interior position of the heteroalkyl group or at theposition at which the alkyl group is attached to the remainder of themolecule. Examples include, but are not limited to, —CH₂—CH₂—O—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,and —CH═CH—N(CH₃)—CH₃. Up to two heteroatoms may be consecutive, suchas, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃. Similarly, the term“heteroalkylene” by itself or as part of another substituent means adivalent radical derived from heteroalkyl, as exemplified, but notlimited by, —CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. Forheteroalkylene groups, heteroatoms can also occupy either or both of thechain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino,alkylenediamino, and the like). Still further, for alkylene andheteroalkylene linking groups, no orientation of the linking group isimplied by the direction in which the formula of the linking group iswritten. For example, the formula —C(O)₂R′— represents both —C(O)₂R′—and —R^(o)C(O)₂—.

The terms “cycloalkyl” and “heterocycloalkyl”, by themselves or incombination with other terms, represent, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl”, respectively. Additionally, forheterocycloalkyl, a heteroatom can occupy the position at which theheterocycle is attached to the remainder of the molecule. Examples ofcycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. In some preferredembodiments, at each occurrence in any formula of the invention,“cycloalkyl” by itself or as part of another substituent is anunsubstituted, fully saturated, cyclic hydrocarbon radical unlessotherwise specified.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” or “C₁₋₄haloalkyl” is mean to include, but is not belimited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent which can be a single ring or multiplerings (preferably from 1 to 3 rings) which are fused together or linkedcovalently. The term “heteroaryl” refers to aryl groups (or rings) thatcontain from one to four heteroatoms selected from N, O, and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaterized. A heteroaryl group can be attached tothe remainder of the molecule through a heteroatom. Non-limitingexamples of aryl and heteroaryl groups include phenyl, 1-naphthyl,2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below. In some preferred embodiments,“aryl” by itself or as part of another substituent denotes a monovalentmonocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbonradical. In yet other preferred embodiments, “aryl” by itself or as partof another substituent denotes a monovalent monocyclic, bicyclic orpolycyclic polyunsaturated unsubstituted aromatic hydrocarbon radicalunless otherwise specified and “heteroaryl” refers to unsubstituted arylgroups (or rings) that contains from one to five heteroatoms selectedfrom N, O, or S, wherein the nitrogen and sulfur atoms are optionallyoxidized, and the nitrogen atom(s) are optionally quaternized unlessotherwise specified.

For brevity, the term “aryl” when used in combination with other terms(e.g., aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroarylrings as defined above. Thus, the term “arylalkyl” is meant to includethose radicals in which an aryl group is attached to an alkyl group(e.g., benzyl, phenethyl, pyridylmethyl and the like) including thosealkyl groups in which a carbon atom (e.g., a methylene group) has beenreplaced by, for example, an oxygen atom (e.g., phenoxymethyl,2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl, and the like).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl” and“heteroaryl”) include both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to: —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″)═NR′″, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and —NO₂ in a number ranging fromzero to (2m′+1), where m′ is the total number of carbon atoms in suchradical. R′, R″, R′″ and R″″ each preferably independently refer tohydrogen, substituted or unsubstituted heteroalkyl, substituted orunsubstituted aryl, e.g., aryl substituted with 1-3 halogens,substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, orarylalkyl groups. When a compound of the invention includes more thanone R group, for example, each of the R groups is independently selectedas are each R′, R″, R′″ and R″″ groups when more than one of thesegroups is present. When R′ and R″ are attached to the same nitrogenatom, they can be combined with the nitrogen atom to form a 5-, 6-, or7-membered ring. For example, —NR′R″ is meant to include, but not belimited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussionof substituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound togroups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: halogen, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″,—SR′, -halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″,—OC(O)NR′R″, —NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —CN and—NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy, and fluoro(C₁-C₄)alkyl,in a number ranging from zero to the total number of open valences onthe aromatic ring system; and where R′, R″, R′″ and R″″ are preferablyindependently selected from hydrogen, (C₁-C₈)alkyl and heteroalkyl,unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(C₁-C₄)alkyl,and (unsubstituted aryl)oxy-(C₁-C₄)alkyl. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″ and R″″ groupswhen more than one of these groups is present.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally be replaced with a substituent of the formula-T-C(O)—(CRR′)_(q)—U—, wherein T and U are independently —NR—, —O—,—CRR′- or a single bond, and q is an integer of from 0 to 3.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula -A-(CH₂)_(r)—B—, wherein A and B are independently —CRR′—, —O—,—NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′- or a single bond, and r is aninteger of from 1 to 4. One of the single bonds of the new ring soformed may optionally be replaced with a double bond. Alternatively, twoof the substituents on adjacent atoms of the aryl or heteroaryl ring mayoptionally be replaced with a substituent of the formula—(CRR′)_(s)—X—(CR″R′″)_(d)—, where s and d are independently integers offrom 0 to 3, and X is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or —S(O)₂NR′—.The substituents R, R′, R″ and R′″ are preferably independently selectedfrom hydrogen or substituted or unsubstituted (C₁-C₆) alkyl.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

As used herein, the term “aryloxy” means a radical —OR′, where R′ is anaryl as defined herein, e.g., phenoxy and the like.

As used herein, the term “carbocyclic ring” means a saturated,unsaturated or partially saturated, mono-, bicyclic or polycyclic ring(preferably 1-3 rings), which contains only carbon ring atoms(preferably 3-14 ring carbon atoms). The carbocyclic ring can benon-aroamatic or aromatic ring. Exemplary carbocyclic rings includecyclopentane ring, cyclohexane ring, benzene ring, naphthalene ring, andthe like.

As used herein, the term “tautomer” means compounds produced by thephenomenon wherein a proton of one atom of a molecule shifts to anotheratom. See, Jerry March, Advanced Organic Chemistry: Reactions,Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages69-74 (1992). The tautomers also refer to one of two or more structuralisomers that exist in equilibrium and are readily converted from oneisomeric form to another. Examples of include keto-enol tautomers, suchas acetone/propen-2-ol, imine-enamine tautomers and the like, ring-chaintautomers, such as glucose/2,3,4,5,6-pentahydroxy-hexanal and the like,the tautomeric forms of heteroaryl groups containing a —N═C(H)—NH— ringatom arrangement, such as pyrazoles, imidazoles, benzimidazoles,triazoles, and tetrazoles. The compounds described herein may have oneor more tautomers and therefore include various isomers. All suchisomeric forms of these compounds are expressly included in the presentinvention.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds which are prepared with relatively nontoxicacids or bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, for example, Berge et al., “Pharmaceutical Salts”, Journal ofPharmaceutical Science, 1977, 66, 1-19). Certain specific compounds ofthe present invention contain both basic and acidic functionalities thatallow the compounds to be converted into either base or acid additionsalts.

When the compound prepared by a method of the invention is apharmacological agent, the salt is preferably a pharmaceuticallyacceptable salt. Examples of pharmaceutically acceptable salts arepresented hereinabove, and are generally known in the art. See, forexample, Wermuth, C., PHARMACEUTICAL SALTS: PROPERTIES, SELECTION ANDUSE—A HANDBOOK, Verlag Helvetica Chimica Acta (2002).

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents, but otherwise the salts are equivalentto the parent form of the compound for the purposes of the presentinvention.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdennal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. “Hydrate” refers toa complex formed by combination of water molecules with molecules orions of the solute. “Solvate” refers to a complex formed by combinationof solvent molecules with molecules or ions of the solute. The solventcan be an organic compound, an inorganic compound, or a mixture of both.Solvate is meant to include hydrate. Some examples of solvents include,but are not limited to, methanol, N,N-dimethylformamide,tetrahydrofuran, dimethylsulfoxide, and water. In general, the solvatedforms are equivalent to unsolvated forms and are encompassed within thescope of the present invention. Certain compounds of the presentinvention may exist in multiple crystalline or amorphous forms. Ingeneral, all physical forms are equivalent for the uses contemplated bythe present invention and are intended to be within the scope of thepresent invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers are encompassed within thescope of the present invention. These isomers can be resolved orasymmetrically synthesized using conventional methods to render theisomers “optically pure”, i.e., substantially free of its other isomers.If, for instance, a particular enantiomer of a compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediasteromers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabelled with radioactive isotopes, such as for example tritium(3H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

The symbol

denotes a point of attachment of a moiety to the remainder of amolecule.

DESCRIPTION OF THE EMBODIMENTS I. Modulators of Voltage-DependentPotassium Channels

In one aspect, the present invention provides compounds of the formula(I):

or a pharmaceutically acceptable salt hydrate, solvate or complexthereofwherein Q, W, Z are members independently selected from carbon andnitrogen, with the proviso that when Q is nitrogen, W and Z are carbon;with the further proviso that when W is nitrogen, Q and Z are carbon;with the further proviso that when Z is nitrogen, Q and W are carbon; Xis a member selected from carbon and nitrogen; Y is a member selectedfrom —(CH₂)_(n)—C(O)—NR⁵—, —(CH₂)_(n)—NR⁵—C(O)—,—(CH₂)_(n)—CR⁶R⁷NR⁵C(O)—, —(CH₂)_(n)—S(O)₂—NR⁵— and—(CH₂)_(n)—NR⁵—S(O)₂—, wherein n is an integer selected from 0, 1, 2, 3,4, 5 and 6; R⁵, R⁶ and R⁷ are members independently selected from H,substituted or unsubstituted C₁-C₇ alkyl group, substituted orunsubstituted aryl and substituted or unsubstituted arylalkyl; R¹ and R²are members independently selected from H, C₁-C₇ substituted orunsubstituted alkyl, CN, CF₃, OCF₃, SCF₃, halogen, thioalkyl, S(O)R⁸,S(O)₂R⁸, C(O)R⁸, C(O)₂R⁸, substituted or unsubstituted benzyl,substituted or unsubstituted phenyl and substituted or unsubstitutedheteroaryl, wherein R⁸ is a member selected from H, substituted orunsubstituted C₁-C₇ alkyl, substituted or unsubstituted benzyl,substituted or unsubstituted phenyl and substituted or unsubstitutedheteroaryl; R³ is a member selected from the group consisting of CF₃,—(CH₂)_(m)CF₃, substituted or unsubstituted C₁-C₉ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl andsubstituted or unsubstituted C₃-C₈ cycloalkyl, wherein m is an integerselected from 0, 1, 2, 3, 4, 5 and 6; R⁴ is a member selected fromsubstituted or unsubstituted C₁-C₉ alkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted C₃-C₉ cyclo or bicyclo alkyl and —(CH₂)_(p)CF₃, wherein pis an integer selected from 0, 1, 2, 3, 4, 5 and 6.

In some embodiments, the compounds of Formula (I) have Formula (II):

wherein Q, W, Z are members independently selected from carbon ornitrogen, with the proviso that when Q is nitrogen, W and Z are carbon;with the further proviso that when W is nitrogen, Q and Z are carbon;with the further proviso that when Z is nitrogen, Q and W are carbon; Xis a member selected from carbon and nitrogen; R¹ and R² are membersindependently selected from H, C₁-C₇ substituted or unsubstituted alkyl,CN, CF₃, OCF₃, SCF₃, halogen, thioalkyl, S(O)R⁹, S(O)₂R⁹, C(O)R⁹,C(O)₂R⁹, substituted or unsubstituted benzyl, substituted orunsubstituted phenyl and substituted or unsubstituted heteroaryl,wherein R⁹ is a member selected from H and substituted or unsubstitutedC₁-C₇ alkyl; R³ is a member selected from CF₃, —(CH₂)_(m)CF₃,substituted or unsubstituted C₁-C₉ alkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted C₃-C₉ cycloalkyl and substituted or unsubstituted C₃-C₉bicycloalkyl; wherein m is an integer selected from 0, 1, 2, 3, 4, 5 and6; R⁴ is a member selected from the group consisting of H, substitutedor unsubstituted C₁-C₈ alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, S(O)₂R¹⁰ and —(CH₂)_(p)CF₃, wherein p is an integerselected from 0, 1, 2, 3, 4, 5 and 6; R¹⁰ is a member selected fromsubstituted or unsubstituted C₁-C₈ alkyl, —(CH₂)_(t)-substituted orunsubstituted aryl, —(CH₂)_(t)-substituted or unsubstituted heteroaryl,—(CH₂)_(t)-substituted or unsubstituted C₃-C₉ cycloalkyl and—(CH₂)_(t)-substituted or unsubstituted C₃-C₉ bicycloalkyl, wherein t isan integer selected from 0, 1, 2, 3, 4, 5 and 6; R⁵ is a member selectedfrom substituted or unsubstituted —(CO)—C₁-C₉ alkyl, substituted orunsubstituted —(CO)—C₁-C₉ alkyl, —(CH₂)_(s)-substituted or unsubstitutedaryl, —(CO)—(CH₂)_(s)-substituted or unsubstituted aryl,—(CO)—(CH₂)_(s)-substituted or unsubstituted heteroaryl,—(CO)—(CH₂)_(s)-substituted or unsubstituted heteroaryl and—(CO)—(CH₂)_(s)-substituted or unsubstituted C₃-C₉ cycloalkyl, wherein sis an integer selected from 0, 1, 2, 3, 4, 5 and 6.

In a first group of embodiments of the compounds having Formula (II), Q,W and Z are carbon and are substituted or unsubstituted.

Within the first group of embodiments or Formula (II), the presentinvention provides a second group of embodiments of compounds, in whichQ, W and Z are carbon and each are independently substituted by one ormore groups selected from halogen, nitrile, substituted or unsubstitutedC₁-C₄ alkyl, trifluoromethyl and trifluoromethoxy.

Within the first, second group of embodiments or Formula (II), theinvention provides a third group of embodiments of compounds, havingFormula (III):

wherein R¹ and R² are members independently selected from H, halogen,CN, CF₃ and OCF₃; R³ is a member selected from —CH₃, —CH₂CH₃, —CH═CH₂—,—CH₂cyclopropyl, cyclopropyl, —CH₂CF₃ and substituted or unsubstitutedphenyl; R⁵ is a member selected from substituted or unsubstituted C₁-C₉alkyl, substituted or unsubstituted —O—C₁-C₉ alkyl,—(CH₂)_(s)-substituted or unsubstituted aryl, —O—(CH₂)_(s)-substitutedor unsubstituted aryl, —(CH₂)_(s)-substituted or unsubstitutedheteroaryl, —O—(CH₂)_(s)-substituted or unsubstituted heteroaryl,—(CH₂)_(s)-substituted or unsubstituted C₃-C₉ cycloalkyl and—O—(CH₂)_(s)-substituted or unsubstituted C₃-C₉ cycloalkyl, wherein s isan integer selected from 0, 1, 2, 3, 4, 5 and 6.

Within the first, second or third group of embodiments or Formulas (II)or (III), the invention provides a fourth group of embodiments of thecompounds, having formula (IV):

wherein R¹ and R² are members independently selected from —CF₃ andhalogen; R³ and R⁴ are members independently selected from H, —CF₃ andhalogen; R⁵ is a member selected from substituted or unsubstituted C₁-C₉alkyl, substituted or unsubstituted —O—C₁-C₉ alkyl,—(CH₂)_(s)-substituted or unsubstituted aryl, —O—(CH₂)_(s)-substitutedor unsubstituted aryl, —(CH₂)_(s)-substituted or unsubstitutedheteroaryl, —O—(CH₂)_(s)-substituted or unsubstituted heteroaryl,—(CH₂)_(s)-substituted or unsubstituted C₃-C₉ cycloalkyl and—O—(CH₂)_(s)-substituted or unsubstituted C₃-C₉ cycloalkyl, wherein s isan integer selected from 0, 1, 2, 3, 4, 5 and 6.In some embodiments, the present invention provides a compound ofFormula (V)

or a pharmaceutically acceptable salt, hydrate, solvate or complexthereof, wherein: X is Nitrogen; Y is a member selected from the group—(CH₂)n—C(O)—NR₅—, —(CH₂)n—NR₅—C(O)—, —(CH₂)n—CR₆R₇NR₅C(O)—,—(CH₂)n—S(O)₂—NR₅—, —(CH₂)n—NR₅—S(O)₂—; wherein R₅, R₆ and R₇ are amember selected from —H, substituted or unsubstituted C₁-C₇ alkyl groupand n is an integer from 0-6, substituted or unsubstituted aryl,substituted or unsubstituted alkyl aryl; R₁ and R₂ are independently —H,C₁-C₇ substituted or unsubstituted alkyl, CN, CF₃, OCF₃, SCF₃, halogen,thioalkyl, S(O)R₈ S(O)₂R₈, C(O)R₈, C(O)₂R₈, optimally substitutedbenzyl, phenyl or heteroaryl; wherein R₈ is a member selected from thegroup consisting of —H and a substituted or unsubstituted C₁-C₇ alkyl,optimally substituted benzyl, phenyl or heteroaryl; group; R₃ is amember selected from the group consisting of CF₃, —(CH₂)nCF₃, wherein nis an integer from 0-6, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl; R₄ is amember selected from the group consisting of substituted orunsubstituted C₁-C₉ alkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₉ cyclo or bicyclo alkyl, or —(CH₂)nCF₃, wherein n is an integerfrom 0-6.

Within Formula (V), the invention provides a first group of embodimentsof compounds, having Formula (VI):

In which: R₁ and R₂ are independently —H, C₁-C₇ substituted orunsubstituted alkyl, CN, CF₃, OCF₃, SCF₃, halogen, thioalkyl, S(O)R₉S(O)₂R₉, C(O)R₉, C(O)₂R₉, optimally substituted benzyl, phenyl orheteroaryl; wherein R₉ is a member selected from —H, substituted orunsubstituted C₁-C₇ alkyl group; R₃ is a member selected from the groupconsisting of CF₃, —(CH₂)nCF₃, wherein n is an integer from 0-6,substituted or unsubstituted C₁-C₉ alkyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted C₃-C₉ cyclo or bicycloalkyl; R₄ is a member selected fromthe group consisting of —H, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, S(O)₂R₁₀ or—(CH₂)nCF₃ wherein n is an integer from 0-6 and R₁₀ is a member selectedfrom substituted or unsubstituted C₁-C₈ alkyl, —(CH₂)n-substituted orunsubstituted aryl, —(CH₂)n-substituted or unsubstituted heteroaryl,—(CH₂)n-substituted or unsubstituted C₃-C₉ cyclo or bicycloalkyl; R₅ isa member selected from substituted or unsubstituted —(CO)—C₁-C₉ alkyl,substituted or unsubstituted —(CO)—C₁-C₉ alkyl, —(CH₂)n-substituted orunsubstituted aryl, —(CO)—(CH₂)n-substituted or unsubstituted aryl,—(CO)—(CH₂)n-substituted or unsubstituted heteroaryl,—(CO)—(CH₂)n-substituted or unsubstituted heteroaryl,—(CO)—(CH₂)n-substituted or unsubstituted C₃-C₉ cycloalkyl.

Within the compounds having Formulas (V) or (VI), the invention providesa second group of embodiments of compounds, in which R₁ and R₂ aregroups selected from halogen, nitrile, substituted or unsubstitutedC₁-C₄ alkyl, trifluoromethyl and trifluoromethoxy.

Within the compounds having Formulas (V) or (VI) or the second group ofembodiments, the invention provides a third group of embodiments ofcompounds, having Formula (VII):

In which R₃ is a member selected from —CH₃, —CH₂CH₃,—CH═CH₂—CH₂cyclopropyl, cyclopropyl or —CH₂CF₃; substituted orunsubstituted phenyl; R₅ is a member selected from substituted orunsubstituted C₁-C₉ alkyl, substituted or unsubstituted —O—C₁-C₈ alkyl,—(CH₂)n-substituted or unsubstituted aryl, —O—(CH₂)n-substituted orunsubstituted aryl, —(CH₂)n-substituted or unsubstituted heteroaryl,—O—(CH₂)n-substituted or unsubstituted heteroaryl, —(CH₂)n-substitutedor unsubstituted C₃-C₉ cycloalkyl, —O—(CH₂)n-substituted orunsubstituted C₃-C₉ cycloalkyl.

Within the compounds having Formulas (V), (VI) or (VII) or the secondgroup of embodiments, the invention provides a fourth group ofembodiments of compounds, having the Formula (VIII)

In which R₃ and R₄ are independently —H, —CF₃, —OCF₃ or halogen; R₅ is amember selected from substituted or unsubstituted C₁-C₉ alkyl,substituted or unsubstituted —O—C₁-C₉ alkyl, —(CH₂)n-substituted orunsubstituted aryl, —O—(CH₂)n-substituted or unsubstituted aryl,—(CH₂)n-substituted or unsubstituted heteroaryl, —O—(CH₂)n-substitutedor unsubstituted heteroaryl, —(CH₂)n-substituted or unsubstituted C₃-C₉cycloalkyl, —O—(CH₂)n-substituted or unsubstituted C₃-C₉ cycloalkyl.

In one group of embodiments, the present invention provide a compound ofFormula (IX):

or a pharmaceutically acceptable salt, hydrate or solvate thereof. Inone instance, R¹⁵ is —H.

In Formula (IX), R¹¹ and R¹² are each independently selected from thegroup consisting of —H, halogen, C₁₋₈haloalkyl, —CN, C₁₋₈alkyl,C₁₋₈alkoxy, aryloxy and aryl-C₁₋₈alkoxy. In one group of embodiments ofcompounds having Formula (IX), R¹¹ is —H, —CH₃, —CF₃, —CN, —OCH₃, —Cl,PhO—, Ph-CH₂CH₂O— or PhCH₂O—. In another group of embodiments ofcompounds having Formula (IX), R¹¹ is —H, —CH₃, —CF₃, —CN, —OCH₃, or—Cl. In yet another group embodiments of compounds having formula (IX),R¹² is —H, —F, —Cl, —Br, —CN, —CH₃, —CF₃, —OCH₃, PhO—, Ph-CH₂CH₂O— orPhCH₂O—. In still another embodiments of compounds having Formula (IX),R¹² is —H, —F, —Cl, —Br, —CN, —CH₃, —CF₃, or —OCH₃. In some embodimentsof compounds having Formula (IX), R¹¹ is —H, —CH₃, —CF₃, —CN, —OCH₃,—Cl, PhO—, Ph-CH₂CH₂O— or PhCH₂O— and R¹² is —H, —F, —Cl, —Br, —CN,—CH₃, —CF₃, —OCH₃, PhO—, Ph-CH₂CH₂O— or PhCH₂O—. In certain instances,R¹² is —H. In other instances, R¹¹ and R¹² are —H.

In Formula (IX), R¹³ is selected from the group consisting of —H,C₁₋₈alkyl, C₂₋₈alkenyl, aryl, C₃₋₈cycloalkyl, aryl-C₁₋₆alkyl,C₃₋₈cycloalkyl-C₁₋₈alkyl, heteroaryl and heteroaryl-C₁₋₆alkyl, whereinthe aromatic portion of the R¹³ group is optionally substituted withfrom 1-3 R^(a) substituents, each R^(a) is independently selected fromthe group consisting of halogen, C₁₋₈haloalkoxy, C₁₋₈alkoxy,C₁₋₈haloalkyl, —CN and R^(b), wherein R^(b) is C₁₋₈alkyl optionallysubstituted with from 1-2 substituents selected from halogen, —CN, —OH,C₁₋₈haloalkoxy or C₁₋₈alkoxy; or any two adjacent R^(a) substituentstogether with the atoms to which they are attached form a 5- or6-membered carbocyclic ring, optionally substituted with a C₁₋₈alkyl.

In one group of embodiments of compounds having Formula (IX), R¹³ isselected from the group consisting of —H, C₁₋₈alkyl, C₂₋₈alkenyl, aryl,C₃₋₈cycloalkyl, aryl-C₁₋₆alkyl, C₃₋₈cycloalkyl-C₁₋₈alkyl and 5- or6-membered heteroaryl having from 1-3 heteroatoms as ring membersselected from N, O or S, wherein the aryl or heteroaryl moiety of theR¹³ group is optionally substituted with from 1-3 R^(a) substituents,each R^(a) is independently selected from the group consisting ofhalogen, —OCF₃, C₁₋₈alkoxy, —CF₃, —CN, hydroxy-C₁₋₈alkyl,C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈haloalkyl, cyano-C₁₋₈alkyl,C₁₋₈haloalkoxy-C₁₋₈alkyl; or optionally any two adjacent R^(a)substituents together with the atoms to which they are attached form a5- or 6-membered carbocyclic ring, optionally substituted with aC₁₋₈alkyl. In certain instances, the carbocyclic ring is a benzene ring,a cyclopentane or cyclohexane ring.

In another group of embodiments of compounds having Formula (IX), R¹³ isselected from the group consisting of: i) —H, halogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₈alkyl; ii) phenyl,benzyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrizinyl, 3-pyridazinyl,4-pyridazinyl, 2-pyrimidinyl or 1,3,5-triazin-2-yl, each of which isoptionally substituted with from 1-3 substituents independently selectedfrom —F, Br, Cl, I, —CH₃, C₁₋₈alkyl, isopropyl, —CF₃, —CN, —C(CH₃)₂CN,—OCF₃, C₁₋₄alkoxy or —CHF₂; and iii) 2-thiazolyl, 4-thiozoly,5-thiazolyl, 2-benzothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl,each of which is optionally substituted with a C₁₋₈alkyl.

In yet another group of embodiments of compounds having Formula (IX),R¹³ is R¹³ is selected from the group consisting of —H, Cl, Br, —I,—CH₃, vinyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,4-difluorophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl,2,6-difluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-pyridyl,3-pyridyl, 4-pyridyl, cyclopropyl, 2,2-dimethylpropyl, 2-fluorobenzyl,3-fluorobenzyl, 4-fluorobenzyl, 3-(2-cyanopropan-2-yl)phenyl,4-(2-cyanopropan-2-yl)phenyl, 6-fluoro-3-pyridyl, 2-fluoro-3-pyridyl,4-fluoro-3-pyridyl, 5-fluoro-3-pyridyl, 6-cyano-3-pyridyl,2-cyano-3-pyridyl, 4-cyano-3-pyridyl, 5-cyano-3-pyridyl, 2-cyanophenyl,3-cyanophenyl, 4-cyanophenyl, 6-fluoro-2-pyridyl, 3-fluoro-2-pyridyl,4-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-trifluoromethyl-2-pyridyl,3-trifluoromethyl-2-pyridyl, 4-trifluoromethyl-2-pyridyl,5-trifluoromethyl-2-pyridyl, 3-difluoromethyl-4-fluorophenyl,3-difluoromethyl-5-fluorophenyl, 3-fluoro-4-difluoromethylphenyl,3-fluoro-4-trifluoromethoxyphenyl, 3-fluoro-5-trifluoromethoxyphenyl,3-fluoro-4-cyanophenyl, 3-fluoro-5-cyanoyphenyl,3-fluoro-4-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl,3-trifluoromethyl-4-fluorophenyl, 3-trifluoromethyl-4-methoxyphenyl,3-trifluoromethyl-5-methoxyphenyl, 3-methoxy-4-trifluoromethylphenyl,3-fluoro-4-methylphenyl, 3-fluoro-5-methylphenyl,3-methyl-4-fluorophenyl, 4-trifluoromethyl-3-pyridyl,5-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl,5-methyl-2-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl,6-methyl-2-pyridyl, benzothiazol-2-yl, 3,4-difluorophenyl,3-5-difluorophenyl, 2-pyrimidinyl, 3-methyl-4-fluorophenyl,3-methyl-5-fluorophenyl, 3-fluoro-4-methylphenyl,3,5-difluoro-4-methylphenyl, 3-methyl-4-chlorophenyl,3-methyl-5-chlorophenyl, 3-chloro-4-methylphenyl, 3-chloro-2-pyridyl,4-chloro-2-pyridyl, 5-chloro-2-pyridyl, 6-chloro-2-pyridyl,3-methoxy-2-pyridyl, 4-methoxy-2-pyridyl, 5-methoxy-2-pyridyl,6-methoxy-2-pyridyl, 1-isopropyl-4-pyrazolyl, cyclohexylmethyl,cyclohexyl, 3-methyl-1-butyl, cyclopentyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-methyl-4-thiazolyl, 5-methyl-2-thiazolyl and4-methyl-2-thiazolyl.

In a preferred group of embodiments of compounds having Formula (IX),R¹³ is C₁₋₈alkyl, C₃₋₈cycloalkyl or C₃₋₈cycloalkyl-C₁₋₄alkyl. In certaininstances, R¹³ is 2-methylbutyl, 2,2-dimethylpropyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, t-butyl or isobutyl. In otherinstances, R¹³ is 2-methylbutyl, 2,2-dimethylpropyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropyl,cyclobutyl, cyclopentyl, or t-butyl.

In Formula (IX), R¹⁴ is selected from the group consisting of C₁₋₈alkyl,C₁₋₈haloalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₈alkyl, aryl,aryl-C₁₋₈alkyl, C₁₋₈alkoxy, aryl-C₁₋₈alkoxy, C₄₋₅heterocycloalkyl,C₄₋₅heterocycloalkyl-C₁₋₈alkyl, R^(c), —NHR^(d) and —N(R^(d))₂, whereinR^(c) is C₁₋₈alkyl substituted with from 1-2 members selected from —OH,—OC(O)C₁₋₈alkyl, —CH₂N(R^(d))₂, —OC(O)aryl, C₁₋₈alkoxy or aryloxy andR^(d) is C₁₋₈alkyl or aryl-C₁₋₈alkyl, wherein the aromatic portion ofthe R¹⁴ group is optionally substituted with from 1-3 R^(e) substituentsindependently selected from the group consisting of halogen,C₁₋₈haloalkyl, C₁₋₈alkyl, C₁₋₈alkoxy, —CN or haloalkoxy, —OH,—OC(O)O—R^(f), —OC(O)R^(f), —OC(O)NHR^(f), —OC(O)N(R^(f))₂, —S(O)R^(f),—S(O)₂R^(f)—SO₂NH₂, —S(O)₂NHR^(f), —S(O)₂N(R^(f))₂, —NHS(O)₂R^(f),—NR^(f)S(O)₂R^(f), —C(O)NH₂, —C(O)NHR^(f), —C(O)N(R^(f))₂, —C(O)R^(f),—C(O)H, wherein each R^(f) is independently a C₁₋₈alkyl; and thecycloalkyl portion of the R¹⁴ group is optionally substituted with from1-3 substituents selected from halogen, C₁₋₈alkyl or optionally fusedwith a 5- or 6-membered aromatic ring having from 0-2 heteroatoms asring members selected from N, O or S.

In one group of embodiments of the compounds having Formula (IX), R¹⁴ isselected from the group consisting of C₁₋₈alkyl, C₁₋₈haloalkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₈alkyl, aryl-C₁₋₈alkyl, C₁₋₈alkoxy,aryl-C₁₋₈alkoxy, C₄₋₅heterocycloalkyl, C₄₋₅heterocycloalkyl-C₁₋₈alkyl,hydroxyl-C₁₋₈alkyl, C₁₋₈alkyl-C(O)O—C₁₋₈alkyl, aryl-C(O)O—C₁₋₈alkyl,C₁₋₈alkoxy-C₁₋₈alkyl or aryloxy-C₁₋₈alkyl, (R^(d))₂NCH₂—C₁₋₈alkyl,—NHR^(d) and —N(R^(d))₂, wherein R^(d) is C₁₋₈alkyl or aryl-C₁₋₈alkyl;wherein the aromatic portion of the R¹⁴ group is optionally substitutedwith from 1-3 substituents selected from the group consisting ofhalogen, C₁₋₈haloalkyl, C₁₋₈alkyl, C₁₋₈alkoxy, —CN or haloalkoxy and thecycloalkyl portion of the R¹⁴ group is optionally substituted with from1-3 substituents selected from halogen, C₁₋₈alkyl or optionally fusedwith a 5- or 6-membered aromatic ring having from 0-2 heteroatoms asring members selected from N, O or S.

In another group of embodiments of the compounds having Formula (IX),R¹⁴ is selected from the group consisting of C₁₋₈alkyl, C₁₋₈haloalkyl,C₁₋₈alkoxy, C₄₋₅heterocycloalkyl, C₄₋₅heterocycloalkyl-C₁₋₈alkyl,hydroxyl-C₁₋₈alkyl, C₁₋₈alkyl-C(O)O—C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl,—NH(C₁₋₈alkyl) and —N(C₁₋₈alkyl)₂, phenyl, phenyl-C₁₋₈alkyl,phenyl-C₁₋₈alkoxy, phenyl-C(O)O—C₁₋₈alkyl, phenoxy-C₁₋₈alkyl or(phenyl-C₁₋₈alkyl)NH—, C₃₋₈cycloalkyl and C₃₋₈cycloalkyl-C₁₋₈alkyl,wherein each phenyl moiety is optionally substituted with from 1-3members independently selected from halogen, —CF₃, —CN, —C₁₋₈alkyl or—C₁₋₈alkoxy; and each cycloalkyl moiety is optionally substituted with1-2 substituents selected from halogen and C₁₋₈alkyl or optionally fusedwith a phenyl ring. In certain instances, R¹⁴ is selected from the groupconsisting of —CH₃, —CF₃, 4-fluorophenyl, 3,4-difluorophenyl, benzyl,2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,2-dimethylpropyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopentylmethyl,Ph(CH₃)CH₂—, cyclopropylmethyl, cyclohexylmethyl, 2-methoxybenzyl,3-methoxybenzyl, 4-methoxybenzyl, PhCH₂CH₂—, 2-trifluoromethylbenzyl,3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2-cyanobenzyl,3-cyanobenzyl, 4-cyanobenzyl, 3,4-difluorobenzyl, 3,5-difluorobenzyl,3,6-difluorobenzyl, 2,6-difluorobenzyl, 2,4,4-trimethylpentyl,2-fluoro-6-chloro-benzyl, 2-fluoro-3-chloro-benzyl,2-fluoro-4-chloro-benzyl, 2-fluoro-5-chloro-benzyl,3-fluoro-4-chlorobenzyl, 3-fluoro-5-chlorobenzyl,3-fluoro-6-chlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl,3,6-dichlorobenzyl, 2,6-dichlorobenzyl, 2-methylbenzyl, 3-methylbenzyl,4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl,2-methyl-3,3,3-trifluoropropyl, benzyloxy, 2-methylbutyl, CN—CH₂CH₂CH₂—,(CH₃)₂CHCH(CH₃)—, 3,3-dimethylbutyl, cyclopropylethyl,4,4,4-trifluorobutyl, (bicyclo[2.2.1]heptan-2-yl)methyl,(1-methylcyclohexyl)methyl, (1-methylcyclopentyl)methyl, (CH₃)₃CCH(OH)—,cyclobutylmethyl, CH₃C(O)OCH₂C(CH₃)₂CH₂—, (OH)CH₂C(CH₃)₂CH₂—,1,1-difluoro-2,2-dimethylpropyl, t-butoxymethyl, t-butoxyethyl,2-(4-fluorophenyl)ethylamino, 4-fluorobenzylamino, t-butylamino,2-cyano-2-methylpropyl, cyclopentylethyl, Ph-O—CH₂—, Ph-O—CH(CH₃)—,4-phenoxybenzyl, PhCH₂OCH₂—, 2-tetrahydropyranyl,3,4-dichlorophenoxymethyl, 3,5-dichlorophenoxymethyl,3,6-dichlorophenoxymethyl, 2,3-dichlorophenoxymethyl,2,4-dichlorophenoxymethyl, 2,5-dichlorophenoxymethyl,2,6-dichlorophenoxymethyl, 2-fluorophenoxyethyl, 3-fluorophenoxyethyl,4-fluorophenoxyethyl, (tetrahydropyran-4-yl)methyl, 3,3-dimethylbutyl,2-trifluoromethoxybenzyl, 3-trifluoromethoxybenzyl,4-trifluoromethoxybenzyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclooctyl, cycloheptyl, 2-indanyl, 1-indanyl, isobutyl,3,3-difluorocyclopentylmethyl, 4,4-difluorocyclohexyl,2,2-difluorocyclopropyl, (R)—CF₃CH(CH₃)CH₂—, (S)—CF₃CH(CH₃)CH₂—,CH₃C(O)OCH(t-butyl)-, HOCH(t-butyl)-, 2-tetrahydrofuranyl,

wherein the wavy line indicates the point of attachment to the rest ofthe molecule.

In a preferred group of embodiments of the compounds having Formula(IX), R¹⁴ is aryl-C₁₋₄alkyl, C₁₋₆alkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₄alkyl, aryl or C₄₋₅cycloalkyl, wherein the arylmoiety is substituted with from 1-2 substituents selected from —F, —CF₃or —OCF₃ and the alkyl portion of the R¹⁴ is optionally substituted withfrom 1-2 substituents selected from —F or —CF₃. In certain instances,R¹⁴ is selected from the group consisting of 3,4-difluorobenzyl,cyclobutyl, —CH(s-OH)-t-Bu, —CH₂-t-Bu, —CH₂CH(CF₃)CH₃,(R)—CH₂CH(CF₃)CH₃, (S)—CH₂CH(CF₃)CH₃, —CH₂CH(CF₃)CH₃, cyclohexylmethyl,—CH(CH₃)CH(CH₃)₂, 4-fluorobenzyl, 3-fluorobenzyl, cyclobutylmethyl,—CH₂CH₂-t-Bu, 4-fluorophenyl, 3,4-difluorophenyl, —CH(CH₃)-t-Bu,(R)-2-tetrahydrofuranyl, —CH₂CH(CH₃)CF₃, cyclopentyl, —CH₂CH₂CF₃,3,3-difluorocyclopentylmethyl, 4,4-difluorocyclohexyl and2,2-difluorocyclopropyl.

In another preferred group of embodiments, R¹³ is 2-methylbutyl,2,2-dimethylpropyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl or isobutyl and R¹⁴ is selected fromthe group consisting of 3,4-difluorobenzyl, cyclobutyl, —CH(s-OH)-t-Bu,—CH₂-t-Bu, —CH₂CH(CF₃)CH₃, (R)—CH₂CH(CF₃)CH₃, (S)—CH₂CH(CF₃)CH₃,—CH₂CH(CF₃)CH₃, cyclohexylmethyl, —CH(CH₃)CH(CH₃)₂, 4-fluorobenzyl,3-fluorobenzyl, cyclobutylmethyl, —CH₂CH₂-t-Bu, 4-fluorophenyl,3,4-difluorophenyl, —CH(CH₃)-t-Bu, (R)-2-tetrahydrofuranyl,—CH₂CH(CH₃)CF₃, cyclopentyl, —CH₂CH₂CF₃, 3,3-difluorocyclopentylmethyl,4,4-difluorocyclohexyl and 2,2-difluorocyclopropyl.

In formula (IX), Z¹ is ═N— or ═C(R¹⁶)— and Z² is ═N— or ═C(R¹⁷)—,wherein R¹⁶ and R¹⁷ are each independently —H, C₁₋₈alkyl, halogen, —CN,C₁₋₈haloalkyl, C₁₋₈haloalkoxy, —OR^(g) or —N(R^(g))₂, wherein R^(g) isindependently —H, C₁₋₈alkyl or aryl-C₁₋₈alkyl, with the proviso that Z¹and Z² are not simultaneously ═N—. In one group of embodiments, R¹⁶ isselected from —H, C₁₋₈alkyl, C₁₋₈haloalkyl, C₁₋₈haloalkoxy, halogen,—OH, C₁₋₈alkoxy or aryl-C₁₋₆alkoxy. In certain instances, R¹⁶ isselected from —H, —F, —CF₃, —OCF₃, —CH₃, —N(CH₃)(CH₂Ph), —OH, C₁₋₄alkoxyor benzyloxy. In another group of embodiments, R¹⁷ is selected from —H,C₁₋₈alkyl, C₁₋₈haloalkyl, C₁₋₈haloalkoxy, halogen, —OH, C₁₋₈alkoxy oraryl-C₁₋₆alkoxy. In certain instances, R¹⁷ is selected from —H, —F,—CF₃, —OCF₃, —CH₃, —N(CH₃)(CH₂Ph), —OH, C₁₋₄alkoxy or benzyloxy. In oneembodiment, R¹⁶ and R¹⁷ are —H.

In one embodiment, R¹¹ and R¹⁶ are —H. In another embodiment, R¹¹ andR¹⁷ are —H. In a preferred embodiments, R¹¹, R¹⁶ and R¹⁷ are —H.

In Formula (IX), R¹⁵ is R¹⁵ is —H, —C₁₋₈alkyl or —C(O)C₁₋₈alkyl. In someembodiments, R¹⁵ is —H.

In the above embodiments of compounds having Formula (IX), at eachoccurrence, “alkyl” by itself or as part of another substituent, is anunsubstituted, fully saturated, straight or branched chain hydrocarbonradical unless specified otherwise; at each occurrence, “cycloalkyl” byitself or as part of another substituent is an unsubstituted, fullysaturated, cyclic hydrocarbon radical unless specified otherwise; and ateach occurrence, “aryl” by itself or as part of another substituent is amonovalent monocyclic, bicyclic or polycyclic polyunsaturated aromatichydrocarbon radical. In some preferred embodiments, “aryl” by itself oras part of another substituent denotes a monovalent monocyclic, bicyclicor polycyclic polyunsaturated unsubstituted aromatic hydrocarbon radicalunless otherwise specified and “heteroaryl” by itself or as part ofanother substituent denotes unsubstituted aryl groups (or rings) thatcontains from one to five heteroatoms selected from N, O, or S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized unless otherwise specified.

Subformula of Formula (IX)

In one group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXa):

wherein the substituents, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are asdefined above in Formula (IX). In certain instances, wherein R¹⁶ and R¹⁷are each independently —H, C₁₋₈alkyl, halogen, —CN, C₁₋₈haloalkyl,C₁₋₈haloalkoxy, —OR^(g) or —N(R^(g))₂, wherein R^(g) is independently—H, C₁₋₈alkyl or aryl-C₁₋₈alkyl. In other instances, R¹⁵ is —H. In yetother instances, R¹¹ is —H, —CH₃, —CF₃, —OCH₃, —Cl, PhO— or PhCH₂O— andR¹² is —H, —F, —Cl, —Br, —CN, —CH₃, —CF₃, PhO—, PhCH₂O— or —OCH₃. Incertain instances, R¹ is —H. In other instances, R¹³ is preferably2-methylbutyl, 2,2-dimethylpropyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, isobutyl or t-butyl.

In a second group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXa-1):

wherein the substituents, R¹¹, R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as definedabove in Formula (IX). In certain instances, R¹ is —H. In certaininstances, R¹³ is preferably 2-methylbutyl, 2,2-dimethylpropyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,isobutyl or t-butyl.

In a third group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXa-2):

wherein the substituents, R¹¹, R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as definedabove in Formula (IX). In certain instances, R¹⁵ is —H. In certaininstances, R¹³ is preferably 2-methylbutyl, 2,2-dimethylpropyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,isobutyl or t-butyl.

In a fourth group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXa-3):

wherein R¹⁸ is selected from the group consisting of halogen,C₁₋₈haloalkoxy, C₁₋₈alkoxy, C₁₋₈haloalkyl, —CN and R^(b). The subscriptm is an integer of 0-3. The substituents, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶ andR¹⁷ are as defined above in Formula (IX). In certain instances, R¹⁵ is—H.

In a fifth group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXa-4):

wherein R¹⁹ is selected from the group consisting of halogen,C₁₋₈haloalkoxy, C₁₋₈alkoxy, C₁₋₈haloalkyl, —CN and R^(b). The subscriptn is an integer of 0-3. The substituents, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶ andR¹⁷ are as defined above in Formula (IX). In certain instances, R¹⁵ is—H.

In a sixth group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXa-5):

wherein the substituents, R¹¹, R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as definedabove in Formula (IX). In certain instances, R¹⁵ is —H. In certaininstances, R¹³ is preferably 2-methylbutyl, 2,2-dimethylpropyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,isobutyl or t-butyl

In a seventh group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXa-6):

wherein R²³ and R²⁴ are each independently —H, C₁₋₈alkyl, halogen,C₁₋₈haloalkyl, —CN, —NH₂, —NHC₁₋₈alkyl, —N(C₁₋₈alkyl)₂ or R^(e); or R²³and R²⁴ are taken together with the atoms to which they are attached toform a 6-membered fused ring. In certain instances, the fused ring is abenzene ring or a pyridine ring. In other instances, R²³ and R²⁴ are —H.Other substituents, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as definedabove in Formula (IX).

In certain instances of the above second to the seventh groups ofembodiments, R¹ is —H, —CH₃, —CF₃, —OCH₃, —Cl, PhO— or PhCH₂O— and R¹²is —H, —F, —Cl, —Br, —CN, —CH₃, —CF₃, PhO—, PhCH₂O— or —OCH₃. In otherinstances, R¹¹, R¹⁶ and R¹⁷ are —H.

In an eighth group of embodiments, the compounds of Formula (IX), orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXa-7):

wherein R^(13a) is selected from 2-methylbutyl, 2,2-dimethylpropyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,isobutyl or t-butyl and R¹¹, R¹², R¹⁴, R¹⁵, R¹⁶ and R¹⁷ are as definedabove in Formula (IX). In certain instances, R^(13a) is cyclopropyl,cyclobutyl, cyclopentyl, or 2,2-dimethylpropyl.

In a ninth group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXb):

wherein substituents R¹¹, R¹², R¹³, R¹⁴ and R¹⁶ are as defined above inFormula (IX). In certain instances, R¹¹ is —H and R¹² is —Cl, —CH₃ or—CF₃. In other instances, R¹¹ and R¹⁶ are —H. In yet other instances,R¹³ is 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl,2-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 2,2-dimethylpropyl,cyclopropylmethyl, cyclopropyl, 2-thiazolyl, benzothiazol-2-yl,6-trifluoromethyl-2-pyridyl, 3-trifluoromethyl-2-pyridyl,4-trifluoromethyl-2-pyridyl or 5-trifluoromethyl-2-pyridyl. In certaininstances, R¹³ is preferably 2-methylbutyl, 2,2-dimethylpropyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,isobutyl or t-butyl.

In a tenth group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXb-1):

wherein substituents R¹¹, R¹³, R¹⁴ and R¹⁶ are as defined above inFormula (IX). In certain instances, R¹¹ is —H. In other instances, R¹¹and R¹⁶ are —H. In yet other instances, R¹³ is 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,2-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl,2-trifluoromethoxyphenyl, 2,2-dimethylpropyl, cyclopropylmethyl,cyclopropyl, 2-thiazolyl, benzothiazol-2-yl,6-trifluoromethyl-2-pyridyl, 3-trifluoromethyl-2-pyridyl,4-trifluoromethyl-2-pyridyl or 5-trifluoromethyl-2-pyridyl. In certaininstances, R¹³ is preferably 2-methylbutyl, 2,2-dimethylpropyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,isobutyl or t-butyl.

In an eleventh group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXb-2):

wherein substituents R¹¹, R¹², R¹⁴ and R¹⁶ are as defined above inFormula (IX). In certain instances, R¹¹ is —H. In other instances, R¹¹and R¹⁶ are —H.

In a twelfth group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXb-3):

wherein substituents R¹¹, R¹², R¹⁴ and R¹⁶ are as defined above inFormula (IX). In certain instances, R¹¹ is —H. In other instances, R¹¹and R¹⁶ are —H.

In a thirteenth group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXb-4):

wherein substituents R¹¹, R¹², R¹⁴ and R¹⁶ are as defined above inFormula (IX). In certain instances, R¹¹ is —H. In other instances, R¹¹and R¹⁶ are —H. The subscript p is an integer of 0-3; and R²⁰ isindependently selected from the group consisting of halogen,C₁₋₈haloalkoxy, C₁₋₈alkoxy, C₁₋₈haloalkyl, —CN and R^(b). In certaininstances, p is 1 or 2 and R²⁰ is independently selected from —F, —Cl,—CF₃, —OCF₃, —CN, or —CH₃.

In a fourteenth group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXb-5):

wherein substituents R¹¹, R¹², R¹⁴ and R¹⁶ are as defined above inFormula (IX). In certain instances, R¹¹ is —H. In other instances, R¹¹and R¹⁶ are —H. The subscript q is an integer of 0-3; and R²¹ isindependently selected from the group consisting of halogen,C₁₋₈haloalkoxy, C₁₋₈alkoxy, C₁₋₈haloalkyl, —CN and R^(b). In certaininstances, q is 1 or 2 and R²¹ is independently selected from —F, —Cl,—CF₃, —OCF₃, —CN or —CH₃. In some instances, the pyridyl group is2-pyridyl, 3-pyridyl or 4-pyridyl.

In certain instances of the above ninth to the fourteenth groups ofembodiments, R¹⁴ is selected from the group consisting of3,4-difluorobenzyl, cyclobutyl, —CH(s-OH)-t-Bu, —CH₂-t-Bu,—CH₂CH(CF₃)CH₃, (R)—CH₂CH(CF₃)CH₃, (S)—CH₂CH(CF₃)CH₃, —CH₂CH(CF₃)CH₃,cyclohexylmethyl, —CH(CH₃)CH(CH₃)₂, 4-fluorobenzyl, 3-fluorobenzyl,cyclobutylmethyl, —CH₂CH₂-t-Bu, 4-fluorophenyl, 3,4-difluorophenyl,—CH(CH₃)-t-Bu, (R)-2-tetrahydrofuranyl, —CH₂CH(CH₃)CF₃, cyclopentyl,—CH₂CH₂CF₃, 3,3-difluorocyclopentylmethyl, 4,4-difluorocyclohexyl and2,2-difluorocyclopropyl.

In the fifteenth group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXc):

wherein substituents R¹¹, R¹², R¹³, R¹⁴ and R¹⁷ are as defined above inFormula (IX). In certain instances, R¹¹ and R¹⁷ are —H. In certaininstances, R¹³ is preferably 2-methylbutyl, 2,2-dimethylpropyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,isobutyl or t-butyl.

In the sixteenth group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXc-1):

wherein substituents R¹¹, R¹³, R¹⁴ and R¹⁷ are as defined above inFormula (IX). In certain instances, R¹¹ and R¹⁷ are —H. In certaininstances, R¹³ is preferably 2-methylbutyl, 2,2-dimethylpropyl,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,isobutyl or t-butyl.

In a seventeenth group of embodiments, the compounds of Formula IX, orpharmaceutically acceptable salts, hydrates or solvates thereof, have asubformula (IXc-2):

wherein substituents R¹¹, R¹³, R¹⁴ and R¹⁷ are as defined above inFormula (IX). The subscript r is an integer of 0-3; and R²² is selectedfrom halogen, C₁₋₈haloalkoxy, C₁₋₈alkoxy, C₁₋₈haloalkyl, —CN or R^(b).In certain instances, R¹¹ and R¹⁷ are —H.

In the above embodiments of the compounds having subformulas IXa, IXa-1,IXa-2, IXa-3, IXa-4, IXa-5, IXa-6, IXa-7, IXb-1, IXb-2, IXb-3, IXb-3,IXb-4, IXb-5, IXc, IXc-1 and IXc-2, at each occurrence, at eachoccurrence, “alkyl” by itself or as part of another substituent, is anunsubstituted, fully saturated, straight or branched chain hydrocarbonradical unless otherwise specified; at each occurrence, “cycloalkyl” byitself or as part of another substituent is an unsubstituted, fullysaturated, cyclic hydrocarbon radical unless specified otherwise; and ateach occurrence, “aryl” by itself or as part of another substituent is amonovalent monocyclic, bicyclic or polycyclic polyunsaturated aromatichydrocarbon radical. In some preferred embodiments, “aryl” by itself oras part of another substituent denotes a monovalent monocyclic, bicyclicor polycyclic polyunsaturated unsubstituted aromatic hydrocarbon radicalunless otherwise specified and “heteroaryl” by itself or as part ofanother substituent denotes unsubstituted aryl groups (or rings) thatcontains from one to five heteroatoms selected from N, O, or S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized unless otherwise specified.

In yet other aspects, also within the scope of the present invention arecompounds of the invention that are poly- or multi-valent species,including, for example, species such as dimers, trimers, tetramers andhigher homologs of the compounds of the invention or reactive analoguesthereof. The poly- and multi-valent species can be assembled from asingle species or more than one species of the invention. For example, adimeric construct can be “homo-dimeric” or “heterodimeric.” Moreover,poly- and multi-valent constructs in which a compound of the inventionor a reactive analogue thereof, can be attached to an oligomeric orpolymeric framework (e.g., polylysine, dextran, hydroxyethyl starch andthe like) are within the scope of the present invention. The frameworkis preferably polyfunctional (i.e. having an array of reactive sites forattaching compounds of the invention). Moreover, the framework can bederivatized with a single species of the invention or more than onespecies of the invention.

In still other aspects, moreover, the present invention includescompounds within a motif described herein, which are functionalized toafford compounds having water-solubility that is enhanced relative toanalogous compounds that are not similarly functionalized. Thus, inthese other aspects, any of the substituents set forth herein can bereplaced with analogous radicals that have enhanced water solubility.For example, it is within the scope of the invention to, for example,replace a hydroxyl group with a diol, or an amine with a quaternaryamine, hydroxy amine or similar more water-soluble moiety. In apreferred embodiment, additional water solubility is imparted bysubstitution at a site not essential for the activity towards the ionchannel of the compounds set forth herein with a moiety that enhancesthe water solubility of the parent compounds. Methods of enhancing thewater-solubility of organic compounds are known in the art. Such methodsinclude, but are not limited to, functionalizing an organic nucleus witha pennanently charged moiety, e.g., quaternary ammonium, or a group thatis charged at a physiologically relevant pH, e.g. carboxylic acid,amine. Other methods include, appending to the organic nucleus hydroxyl-or amine-containing groups, e.g. alcohols, polyols, polyethers, and thelike. Representative examples include, but are not limited to,polylysine, polyethyleneimine, poly(ethyleneglycol) andpoly(propyleneglycol). Suitable functionalization chemistries andstrategies for these compounds are known in the art. See, for example,Dunn, R. L., et al., Eds. Polymeric Drugs and Drug Delivery Systems, ACSSymposium Series Vol. 469, American Chemical Society, Washington, D.C.1991.

II. Preparation of the Compounds

Compounds of the present invention can be prepared using readilyavailable starting materials or known intermediates. The syntheticschemes set forth below provide exemplary synthetic pathways for thepreparation of compounds of the invention.

As shown in the Schemes and Examples below, there are a variety ofsynthetic routes by which a skilled artisan can prepare compounds andintermediates of the present invention. Other routes or modification ofthe routes presented below would be readily apparent to a skilledartisan and within the scope of the present invention. Scheme 1 and 2illustrate two general synthetic approaches for compounds as describedherein, for example, compounds of Formulas I, II, III, IV, V, VI, VII,VIII, IX, IXa, IXa-1, IXa-2, IXa-3, IXa-4, IXa-5, IXa-6, IXa-7, IXb-1,IXb-2, IXb-3, IXb-3, IXb-4, IXb-5, IXc, IXc-1 and IXc-2 and compoundsset forth in Examples 1-5 and Tables 1-5. These compounds can beprepared according the procedures set forth in reaction Schemes 1-2 andsynthetic methods 1-5. In Schemes 1 and 2, L is a leaving group, such as—Cl, —Br, —I or tosylate; R′ and R″ are non-interfering substituents; Xis a halo group; and R¹³Q is an organoborane or an organozinc compound,wherein Q can be —B(OH)₂, —B(OR′)₂, —ZnX or other suitable agents. Othersubstituents are as defined above in Formula (IX).

In Scheme 1, the starting material (aa) is either commercially availableor can be readily prepared according the literature procedures. Thefused imidazole ring in the key intermediate (ee) can be prepared bycyclization of intermediate (cc) in the presence of trifluoro aceticacid. Intermediate (cc) can be prepared by reacting compound (aa) withTsCl to form compound (bb), which is further reacted with a substitutedamide, L-CH₂C(O)NH₂. The precursor compound (gg) can be prepared byeither directly reacting with R¹³X in the presence of a palladiumcomplex or converting to intermediates (ff) and (dd), which are furtherreacted with R¹³Q/palladium complex and iodoalkane/BuLi, respectively.Subsequent hydrolysis of precursor compound (gg) produces compound (hh),which is further reacted with an acyl chloride, Cl—C(O)R¹⁴ to yieldcompound (IX).

Alternatively, as shown in Scheme 2, the fused imidazole ring in keyintermediate (ee′) can be prepared by reacting compound (aa) withcompound (jj) under a reflux condition. Subsequent transformations ofintermediate (ee′) to compound (nn) are similar to those described inScheme 1. The formation of precursor compound (oo) is accomplished byhydrolyzing compound (nn) and reacting with diphenylphosphonic azide.Subsequent hydrolysis of precursor compound (oo) yields compound (hh),which is reacted with ClC(O)R¹⁴ to produce compound (IX).

Accordingly, in a first set of embodiments, the present inventionprovides a compound of Formula (IX):

or a pharmaceutically acceptable salt, hydrate or solvate thereof,R¹¹ and R¹² are each independently selected from the group consisting of—H, halogen, C₁₋₈haloalkyl, —CN, C₁₋₈alkyl, C₁₋₈alkoxy, aryloxy andaryl-C₁₋₈alkoxy;R¹³ is selected from the group consisting of —H, C₁₋₈alkyl, C₂₋₈alkenyl,aryl, C₃₋₈cycloalkyl, aryl-C₁₋₆alkyl, C₃₋₈cycloalkyl-C₁₋₈alkyl,heteroaryl and heteroaryl-C₁₋₆alkyl, wherein the aromatic portion of theR¹³ group is optionally substituted with from 1-3 R^(a) substituents,each R^(a) is independently selected from the group consisting ofhalogen, C₁₋₈haloalkoxy, C₁₋₈alkoxy, C₁₋₈haloalkyl, —CN and R^(b),wherein R^(b) is C₁₋₈alkyl optionally substituted with from 1-2substituents selected from halogen, —CN, —OH, C₁₋₈haloalkoxy orC₁₋₈alkoxy; or any two adjacent R^(a) substituents together with theatoms to which they are attached form a 5- or 6-membered carbocyclicring, optionally substituted with a C₁₋₈alkyl;R¹⁴ is selected from the group consisting of C₁₋₈alkyl, C₁₋₈haloalkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₈alkyl, aryl, aryl-C₁₋₈alkyl,C₁₋₈alkoxy, aryl-C₁₋₈alkoxy, C₅₋₆heterocycloalkyl,C₅₋₆heterocycloalkyl-C₁₋₈alkyl, R^(c), —NHR^(d) and —N(R^(d))₂, whereinR^(c) is C₁₋₈alkyl substituted with from 1-2 members selected from —OH,CH₂N(R^(d))₂, —OC(O)C₁₋₈alkyl, —OC(O)aryl, C₁₋₈alkoxy or aryloxy andR^(d) is C₁₋₈alkyl or aryl-C₁₋₈alkyl, wherein the aromatic portion ofthe R¹⁴ group is optionally substituted with from 1-3 R^(e) substituentsindependently selected from the group consisting of halogen,C₁₋₈haloalkyl, C₁₋₈alkyl, C₁₋₈alkoxy, —CN or haloalkoxy, —OH,—OC(O)O—R^(f), —OC(O)R^(f), —OC(O)NHR^(f), —OC(O)N(R^(f))₂, —S(O)R^(f),—S(O)₂R^(f), —SO₂NH₂, —S(O)₂NHR^(f), —S(O)₂N(R^(f))₂, —NHS(O)₂R^(f),—NR^(f)S(O)₂R^(f), —C(O)NH₂, —C(O)NHR^(f), —C(O)N(R^(f))₂, —C(O)R^(f),—C(O)H, wherein each R^(f) is independently a C₁₋₈alkyl; and thecycloalkyl portion of the R¹⁴ group is optionally substituted with from1-3 substituents selected from halogen, C₁₋₈alkyl or optionally fusedwith a 5- or 6-membered aromatic ring having from 0-2 heteroatoms asring members selected from N, O or S;R¹⁵ is —H or —C(O)C₁₋₈alkyl;Z¹ is ═N— or ═C(R¹⁶)— and Z² is ═N— or ═C(R¹⁷)—, wherein R¹⁶ and R¹⁷ areeach independently —H, C₁₋₈alkyl, halogen, —CN, C₁₋₈haloalkyl, C₁haloalkoxy, —OR^(g) or —N(R^(g))₂, wherein R^(g) is independently —H,C₁₋₈alkyl or aryl-C₁₋₈alkyl, with the proviso that Z¹ and Z² are notsimultaneously ═N—;at each occurrence, “alkyl” by itself or as part of another substituent,is an unsubstituted, fully saturated, straight or branched chainhydrocarbon radical unless specified otherwise;at each occurrence, “cycloalkyl” by itself or as part of anothersubstituent is an unsubstituted, fully saturated, cyclic hydrocarbonradical unless specified otherwise; andat each occurrence, “aryl” by itself or as part of another substituentis a monovalent monocyclic, bicyclic or polycyclic polyunsaturatedunsubstituted aromatic hydrocarbon radical. In some preferredembodiments, “aryl” by itself or as part of another substituent denotesa monovalent monocyclic, bicyclic or polycyclic polyunsaturatedunsubstituted aromatic hydrocarbon radical unless otherwise specifiedand “heteroaryl” by itself or as part of another substituent denotesunsubstituted aryl groups (or rings) that contains from one to fiveheteroatoms selected from N, O, or S, wherein the nitrogen and sulfuratoms are optionally oxidized, and the nitrogen atom(s) are optionallyquaternized unless otherwise specified

In a second set of embodiments, the invention provides compounds of thefirst set, wherein R¹⁵ is —H.

In a third set of embodiments, the invention provides compounds of thefirst set, wherein the compounds have Formula (IXa):

wherein R¹⁶ and R¹⁷ are each independently —H, C₁₋₈alkyl, halogen, —CN,C₁₋₈haloalkyl, C₁₋₈haloalkoxy, —OR^(g) or —N(R^(g))₂, wherein R^(g) isindependently —H, C₁₋₈alkyl or aryl-C₁₋₈alkyl.

In a fourth set of embodiments, the invention provides compounds of thethird set, wherein R¹⁵ is —H.

In a fifth set of embodiments, the invention provides compounds of thefirst set or the third set, wherein the compounds have a formulaselected from the group consisting of:

wherein R¹⁶ and R¹⁷ are each independently —H, C₁₋₈alkyl, halogen, CN,C₁₋₈haloalkyl, C₁₋₈haloalkoxy, —OR^(g) or —N(R^(g))₂, wherein R^(g) isindependently —H, C₁₋₈alkyl or aryl-C₁₋₈alkyl; the subscripts m and nare each independently an integer of 0-3; R^(13a) is selected from thegroup consisting of cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl and2,2-dimethylpropyl; R¹⁸ and R¹⁹ are each independently selected from thegroup consisting of halogen, C₁₋₈haloalkoxy, C₁₋₈alkoxy, C₁₋₈haloalkyl,—CN and R^(b); and R²³ and R²⁴ are each independently —H, C₁₋₈alkyl,halogen, C₁₋₈haloalkyl, —CN, —NH₂, —NHC₁₋₈alkyl, —N(C₁₋₈alkyl)₂ orR^(e).

In a sixth set of embodiments, the invention provides compounds of thefifth set, wherein R¹⁵ is —H.

In a seventh set of embodiments, the invention provides compounds of thefirst set, wherein the compounds have Formula (IXb):

In an eighth set of embodiments, the invention provides compounds of thefirst set or the seventh set, wherein the compounds have a Formulaselected from:

wherein the subscripts p and q are each independently an integer of 0-3;and R²⁰ and R²¹ are each independently selected from the groupconsisting of halogen, C₁₋₈haloalkoxy, C₁₋₈alkoxy, C₁₋₈haloalkyl, —CNand R^(b).

In a ninth set of embodiments, the invention provides compounds of thefirst set, wherein the compounds have Formula (IXc):

In a 10th set of embodiments, the invention provides compounds of thefirst set or the ninth set, wherein the subscript r is an integer of0-3; and R²² is selected from halogen, C₁₋₈haloalkoxy, C₁₋₈alkoxy,C₁₋₈haloalkyl, —CN or R^(b).

In an 11th set of embodiments, the invention provides compounds of anyone of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and 11, wherein R¹¹ is —H,—CH₃, —CF₃, —CN, —OCH₃, —Cl, PhO—, Ph-CH₂CH₂O— or PhCH₂O—.

In a 12th set of embodiments, the invention provides compounds of anyone of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, and 11, wherein R¹² is —H, —F,—Cl, —Br, —CN, —CH₃, —CF₃, —OCH₃, PhO—, Ph-CH₂CH₂O— or PhCH₂O—.

In a 13th set of embodiments, the invention provides compounds of anyone of sets 1, 2, 3, 4, 5, and 6, wherein R¹¹ is —H, —CH₃, —CF₃, —OCH₃,—Cl, PhO— or PhCH₂O— and R¹² is —H, —F, —Cl, —Br, —CN, —CH₃, —CF₃, PhO—,PhCH₂O— or —OCH₃.

In a 14th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, and 9, wherein R¹¹ is —H and R¹² is —Cl,—CH₃ or —CF₃.

In a 15th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, and 14, wherein R¹⁶ is selectedfrom —H, C₁₋₈alkyl, C₁₋₈haloalkyl, C₁₋₈haloalkoxy, halogen, —OH,C₁₋₈alkoxy or aryl-C₁₋₆alkoxy.

In a 16th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 9, 10, 11, 12, 13, 14, and 15 wherein R¹⁷ isselected from —H, C₁₋₈alkyl, C₁₋₈haloalkyl, C₁₋₈haloalkoxy, halogen,—OH, C₁₋₈alkoxy or aryl-C₁₋₆alkoxy.

In a 17th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 11, 12, 13, 14, 15 and 16, wherein R¹⁶ isselected from —H, —F, —CF₃, —OCF₃, —CH₃, —N(CH₃)(CH₂Ph), —OH, C₁₋₄alkoxyor benzyloxy.

In a 18th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 9, 10, 11, 12, 13, 14, 15, 16 and 17, wherein R¹⁷is selected from —H, —F, —CF₃, —OCF₃, —CH₃, —N(CH₃)(CH₂Ph), —OH,C₁₋₄alkoxy or benzyloxy.

In a 19th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18,wherein R¹⁶ and R¹⁷ are —H.

In a 20th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and19, wherein R¹³ is selected from the group consisting of —H, C₁₋₈alkyl,C₂₋₈alkenyl, aryl, C₃₋₈cycloalkyl, aryl-C₁₋₆alkyl,C₃₋₈cycloalkyl-C₁₋₈alkyl and 5- or 6-membered heteroaryl having from 1-3heteroatoms as ring members selected from N, O or S, wherein the aryl orheteroaryl moiety of the R¹³ group is optionally substituted with from1-3 R^(a) substituents, each R^(a) is independently selected from thegroup consisting of halogen, —OCF₃, C₁₋₈alkoxy, —CF₃, —CN,hydroxy-C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈haloalkyl, cyano-C₁₋₈alkyl,C₁₋₈haloalkoxy-C₁₋₈alkyl; or optionally any two adjacent R^(a)substituents together with the atoms to which they are attached form a5- or 6-membered carbocyclic ring, optionally substituted with aC₁₋₈alkyl.

In a 21st set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,and 20, wherein R¹³ is selected from the group consisting of: i) —H,halogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₈alkyl; ii) phenyl, benzyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrizinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl or1,3,5-triazin-2-yl, each of which is optionally substituted with from1-3 substituents independently selected from —F, Br, Cl, I, —CH₃,C₁₋₈alkyl, isopropyl, —CF₃, —CN, —C(CH₃)₂CN, —OCF₃, C₁₋₄alkoxy or —CHF₂;and iii) 2-thiazolyl, 4-thiozoly, 5-thiazolyl, 2-benzothiazolyl,3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, each of which is optionallysubstituted with a C₁₋₈alkyl.

In a 22nd set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, and 21, wherein R¹³ is selected from the group consisting of —H, Cl,Br, —I, —CH₃, vinyl, phenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 2,4-difluorophenyl, 2,3-difluorophenyl,2,5-difluorophenyl, 2,6-difluorophenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl,4-trifluoromethoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, cyclopropyl,2,2-dimethylpropyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,3-(2-cyanopropan-2-yl)phenyl, 4-(2-cyanopropan-2-yl)phenyl,6-fluoro-3-pyridyl, 2-fluoro-3-pyridyl, 4-fluoro-3-pyridyl,5-fluoro-3-pyridyl, 6-cyano-3-pyridyl, 2-cyano-3-pyridyl,4-cyano-3-pyridyl, 5-cyano-3-pyridyl, 2-cyanophenyl, 3-cyanophenyl,4-cyanophenyl, 6-fluoro-2-pyridyl, 3-fluoro-2-pyridyl,4-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-trifluoromethyl-2-pyridyl,3-trifluoromethyl-2-pyridyl, 4-trifluoromethyl-2-pyridyl,5-trifluoromethyl-2-pyridyl, 3-difluoromethyl-4-fluorophenyl,3-difluoromethyl-5-fluorophenyl, 3-fluoro-4-difluoromethylphenyl,3-fluoro-4-trifluoromethoxyphenyl, 3-fluoro-5-trifluoromethoxyphenyl,3-fluoro-4-cyanophenyl, 3-fluoro-5-cyanoyphenyl,3-fluoro-4-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl,3-trifluoromethyl-4-fluorophenyl, 3-trifluoromethyl-4-methoxyphenyl,3-trifluoromethyl-5-methoxyphenyl, 3-methoxy-4-trifluoromethylphenyl,3-fluoro-4-methylphenyl, 3-fluoro-5-methylphenyl,3-methyl-4-fluorophenyl, 4-trifluoromethyl-3-pyridyl,5-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl,5-methyl-2-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl,6-methyl-2-pyridyl, benzothiazol-2-yl, 3,4-difluorophenyl,3-5-difluorophenyl, 2-pyrimidinyl, 3-methyl-4-fluorophenyl,3-methyl-5-fluorophenyl, 3-fluoro-4-methylphenyl,3,5-difluoro-4-methylphenyl, 3-methyl-4-chlorophenyl,3-methyl-5-chlorophenyl, 3-chloro-4-methylphenyl, 3-chloro-2-pyridyl,4-chloro-2-pyridyl, 5-chloro-2-pyridyl, 6-chloro-2-pyridyl,3-methoxy-2-pyridyl, 4-methoxy-2-pyridyl, 5-methoxy-2-pyridyl,6-methoxy-2-pyridyl, 1-isopropyl-4-pyrazolyl, cyclohexylmethyl,cyclohexyl, 3-methyl-1-butyl, cyclopentyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-methyl-4-thiazolyl, 5-methyl-2-thiazolyl and4-methyl-2-thiazolyl.

In a 23rd set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, and 22, wherein R¹³ is 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,2-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl,2-trifluoromethoxyphenyl, 2,2-dimethylpropyl, cyclopropylmethyl,cyclopropyl, 2-thiazolyl, benzothiazol-2-yl,6-trifluoromethyl-2-pyridyl, 3-trifluoromethyl-2-pyridyl,4-trifluoromethyl-2-pyridyl or 5-trifluoromethyl-2-pyridyl.

In a 24th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 19,20, 21, 22, and 23, wherein R¹³ is 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl,4-trifluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl or4-chlorophenyl.

In a 25th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, and 21, wherein R¹³ is C₁₋₈alkyl, C₃₋₈cycloalkyl orC₃₋₈cycloalkyl-C₁₋₄alkyl.

In a 26th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, and 25, wherein R¹³ is selected from the groupconsisting of 2-methylbutyl, 2,2-dimethylpropyl, cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl or isobutyl.

In a 27th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, and 26, wherein R¹⁴ is selected from the groupconsisting of C₁₋₈alkyl, C₁₋₈haloalkyl, C₃₋₈cycloalkyl,C₃₋₈cycloalkyl-C₁₋₈alkyl, aryl-C₁₋₈alkyl, C₁₋₈alkoxy, aryl-C₁₋₈alkoxy,C₅₋₆heterocycloalkyl, C₅₋₆heterocycloalkyl-C₁₋₈alkyl,hydroxyl-C₁₋₈alkyl, C₁₋₈alkyl-C(O)O—C₁₋₁₈alkyl, aryl-C(O)O—C₁₋₈alkyl,C₁₋₈alkoxy-C₁₋₈alkyl or aryloxy-C₁₋₈alkyl, —NHR^(d) and —N(R^(d))₂,wherein R^(d) is C₁₋₈alkyl or aryl-C₁₋₈alkyl; wherein the aromaticportion of the R¹⁴ group is optionally substituted with from 1-3substituents selected from the group consisting of halogen,C₁₋₈haloalkyl, C₁₋₈alkyl, C₁₋₈alkoxy, —CN or haloalkoxy and thecycloalkyl portion of the R¹⁴ group is optionally substituted with from1-3 substituents selected from halogen, C₁₋₈alkyl or optionally fusedwith a 5- or 6-membered aromatic ring having from 0-2 heteroatoms asring members selected from N, O or S.

In a 28th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, and 27, R¹⁴ is selected from the groupconsisting of C₁₋₈alkyl, C₁₋₈haloalkyl, C₁₋₈alkoxy,C₅₋₆heterocycloalkyl, C₄₋₅heterocycloalkyl-C₁₋₈alkyl,hydroxyl-C₁₋₈alkyl, C₁₋₈alkyl-C(O)O—C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl,—NH(C₁₋₈alkyl) and —N(C₁₋₈alkyl)₂, phenyl, phenyl-C₁₋₈alkyl,phenyl-C₁₋₈alkoxy, phenyl-C(O)O—C₁₋₈alkyl, phenoxy-C₁₋₈alkyl or(phenyl-C₁₋₈alkyl)NH—, C₃₋₈cycloalkyl and C₃₋₈cycloalkyl-C₁₋₈alkyl,wherein each phenyl moiety is optionally substituted with from 1-3members independently selected from halogen, —CF₃, —CN, —C₁₋₈alkyl or—C₁₋₈alkoxy; and each cycloalkyl moiety is optionally substituted with1-2 substituents selected from halogen and C₁₋₈alkyl or optionally fusedwith a phenyl ring.

In a 29th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, and 28, wherein R¹⁴ is selected from thegroup consisting of —CH₃, —CF₃, 4-fluorophenyl, 3,4-difluorophenyl,benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,2,2-dimethylpropyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl,cyclopentylmethyl, Ph(CH₃)CH₂—, cyclopropylmethyl, cyclohexylmethyl,2-methoxybenzyl, 3-methoxybenzyl, 4-methoxybenzyl, PhCH₂CH₂—,2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4-cyanobenzyl,3,4-difluorobenzyl, 3,5-difluorobenzyl, 3,6-difluorobenzyl,2,6-difluorobenzyl, 2,4,4-trimethylpentyl, 2-fluoro-6-chloro-benzyl,2-fluoro-3-chloro-benzyl, 2-fluoro-4-chloro-benzyl,2-fluoro-5-chloro-benzyl, 3-fluoro-4-chlorobenzyl,3-fluoro-5-chlorobenzyl, 3-fluoro-6-chlorobenzyl, 3,4-dichlorobenzyl,3,5-dichlorobenzyl, 3,6-dichlorobenzyl, 2,6-dichlorobenzyl,2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-chlorobenzyl,3-chlorobenzyl, 4-chlorobenzyl, 2-methyl-3,3,3-trifluoropropyl,benzyloxy, 2-methylbutyl, CN—CH₂CH₂CH₂—, (CH₃)₂CHCH(CH₃)—,3,3-dimethylbutyl, cyclopropylethyl, 4,4,4-trifluorobutyl,(bicyclo[2.2.1]heptan-2-yl)methyl, (1-methylcyclohexyl)methyl,(1-methylcyclopentyl)methyl, (CH₃)₃CCH(OH)—, cyclobutylmethyl,CH₃C(O)OCH₂C(CH₃)₂CH₂—, (OH)CH₂C(CH₃)₂CH₂—,1,1-difluoro-2,2-dimethylpropyl, t-butoxymethyl, t-butoxyethyl,2-(4-fluorophenyl)ethylamino, 4-fluorobenzylamino, t-butylamino,2-cyano-2-methylpropyl, cyclopentylethyl, Ph-O—CH₂—, Ph-O—CH(CH₃)—,4-phenoxybenzyl, PhCH₂OCH₂—, 2-tetrahydropyranyl,3,4-dichlorophenoxymethyl, 3,5-dichlorophenoxymethyl,3,6-dichlorophenoxymethyl, 2,3-dichlorophenoxymethyl,2,4-dichlorophenoxymethyl, 2,5-dichlorophenoxymethyl,2,6-dichlorophenoxymethyl, 2-fluorophenoxyethyl, 3-fluorophenoxyethyl,4-fluorophenoxyethyl, (tetrahydropyran-4-yl)methyl, 3,3-dimethylbutyl,2-trifluoromethoxybenzyl, 3-trifluoromethoxybenzyl,4-trifluoromethoxybenzyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclooctyl, cycloheptyl, 2-indanyl, 1-indanyl, isobutyl,3,3-difluorocyclopentylmethyl, 4,4-difluorocyclohexyl,2,2-difluorocyclopropyl, (R)—CF₃CH(CH₃)CH₂—, (S)—CF₃CH(CH₃)CH₂—,CH₃C(O)OCH(t-butyl)-, HOCH(t-butyl)-, 2-tetrahydrofuranyl,

wherein the wavy line indicates the point of attachment to the rest ofthe molecule.

In a 30th set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, and 29, wherein R¹⁴ is selected fromthe group consisting of 3,4-difluorobenzyl, cyclobutyl, —CH(s-OH)-t-Bu,—CH₂-t-Bu, —CH₂CH(CF₃)CH₃, (R)—CH₂CH(CF₃)CH₃, (S)—CH₂CH(CF₃)CH₃,—CH₂CH(CF₃)CH₃, cyclohexylmethyl, —CH(CH₃)CH(CH₃)₂, 4-fluorobenzyl,3-fluorobenzyl, cyclobutylmethyl, —CH₂CH₂-t-Bu, 4-fluorophenyl,3,4-difluorophenyl, —CH(CH₃)-t-Bu, (R)-2-tetrahydrofuranyl,—CH₂CH(CH₃)CF₃, cyclopentyl, —CH₂CH₂CF₃, 3,3-difluorocyclopentylmethyl,4,4-difluorocyclohexyl and 2,2-difluorocyclopropyl.

In a 31st set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30, wherein R¹¹, R¹⁶ and R¹⁷are —H.

In a 32nd set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, and 31, wherein R¹¹ and R¹⁶are —H.

In a 33rd set of embodiments, the invention provides compounds of any ofsets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, and 32, wherein R¹¹ andR¹⁷ are —H.

In another aspect, the invention provides a pharmaceutical compositionincluding/comprising: a compound of any one of the above sets (i.e.,sets 1 to 33) and a pharmaceutically acceptable excipient.

In the sets 1-33 embodiments above, at each occurrence, “alkyl” byitself or as part of another substituent, is an unsubstituted, fullysaturated, straight or branched chain hydrocarbon radical unlessspecified otherwise; at each occurrence, “cycloalkyl” by itself or aspart of another substituent is an unsubstituted, fully saturated, cyclichydrocarbon radical unless specified otherwise; and at each occurrence,“aryl” by itself or as part of another substituent is a monovalentmonocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbonradical. In some preferred embodiments, “aryl” by itself or as part ofanother substituent denotes a monovalent monocyclic, bicyclic orpolycyclic polyunsaturated unsubstituted aromatic hydrocarbon radicalunless otherwise specified and “heteroaryl” by itself or as part ofanother substituent denotes unsubstituted aryl groups (or rings) thatcontains from one to five heteroatoms selected from N, O, or S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized unless otherwise specified.

In another aspect, the invention provides a method of modulatingactivity of a potassium ion channel in a subject, said methodcomprising/including: administering to said subject in need thereof aneffective amount of a compound of any of sets 1-33 to modulate theactivity of a potassium channel.

In a further aspect, the invention provides a method of increasing ionflow through voltage dependent potassium channels in a cell, said methodcomprising/including: contacting the cell with a compound of any of sets1-33 in an amount sufficient to modulate the potassium ion channels.

In another aspect, the present invention provides a method of treating,preventing, inhibiting or ameliorating a central or peripheral nervoussystem disorder or condition through modulation of a potassium ionchannel, said method comprising/including: administering to a subject inneed of such treatment an effective amount of a compound of any of sets1-33. In some embodiments, the disorder or condition is selected fromthe group consisting of migraine, ataxia, Parkinson's disease, bipolardisorders, trigeminal neuralgia, spasticity, mood disorders, braintumors, psychotic disorders, myokymia, seizures, epilepsy, stroke,hearing and vision loss, Alzheimer's disease, age-related memory loss,learning deficiencies, anxiety, motor neuron diseases and urinaryincontinence

In yet another aspect, the present invention provides a method oftreating a member selected from epilepsy, retinal degeneration, pain,anxiety, neuronal degeneration and bipolar disorder through modulationof a voltage-dependent potassium channel, said method comprisingadministering to a subject in need of such treatment, an effectiveamount of a compound of any of sets 1-33. In some embodiments, thecondition or disorder is selected from epilepsy, seizure, retinaldegeneration, pain, anxiety, neuronal degeneration, hearing loss andbipolar disorder. In certain instances, the pain is a member selectedfrom neuropathic pain, diabetic pain, somatic pain, cutaneous pain,visceral pain, inflammatory pain, cancer pain, migraine pain, ormusculoskeletal pain. In one instance, the condition or disorder isepilepsy or seizures. In another instance, the condition or disorder ishearing loss. In yet other instance, the condition or disorder is painor anxiety. In still other instance, condition or disorder is neuronaldegeneration. In another instance, the condition or disorder is retinaldegeneration.

III. Assays for Modulators of KCNQ Channels

Assays for determining the ability of a compound of the invention toopen a potassium ion channel are generally known in the art. One ofskill in the art is able to determine an appropriate assay forinvestigating the activity of a selected compound of the inventiontowards a particular ion channel. For simplicity, portions of thefollowing discussion focuses on KCNQ2 as a representative example,however, the discussion is equally applicable to other potassium ionchannels.

KCNQ monomers as well as KCNQ alleles and polymorphic variants aresubunits of potassium channels. The activity of a potassium channelcomprising KCNQ subunits can be assessed using a variety of in vitro andin vivo assays, e.g., measuring current, measuring membrane potential,measuring ion flux, e.g., potassium or rubidium, measuring potassiumconcentration, measuring second messengers and transcription levels,using potassium-dependent yeast growth assays, and using e.g.,voltage-sensitive dyes, radioactive tracers, and patch-clampelectrophysiology.

Furthermore, such assays can be used to test for activators of channelscomprising KCNQ. As discussed elsewhere herein, activators (openers) ofa potassium channel are useful for treating various disordersattributable to potassium channels. Such modulators are also useful forinvestigation of the channel diversity provided by KCNQ and theregulation/modulation of potassium channel activity provided by KCNQ.

Putative modulators of the potassium channels of the present invention,such as compounds of any of Formulas I, II, III, IV, V, VI, VII, VIII,IX, IXa, IXa-1, IXa-2, IXa-3, IXa-4, IXa-5, IXa-6, IXa-7, IXb-1, IXb-2,IXb-3, IXb-3, IXb-4, IXb-5, IXc, IXc-1 and IXc-2 or a compound of any ofsets 1-33 are tested using biologically active KCNQ, either recombinantor naturally occurring, or by using native cells, like cells from thenervous system expressing the M-current. KCNQ can be isolated,co-expressed or expressed in a cell, or expressed in a membrane derivedfrom a cell. In such assays, KCNQ2 is expressed alone to form ahomomeric potassium channel or is co-expressed with a second subunit(e.g., another KCNQ family member, preferably KCNQ3) so as to form aheteromeric potassium channel. Modulation is tested using one of the invitro or in vivo assays described above. Samples or assays that aretreated with a potential potassium channel activator are compared tocontrol samples without the test compound, to examine the extent ofmodulation. Control samples (untreated with activators) are assigned arelative potassium channel activity value of 100. Activation of channelscomprising KCNQ2 is achieved when the potassium channel activity valuerelative to the control is 110%, more preferably 130%, more preferably170% higher. Compounds that increase the flux of ions will cause adetectable increase in the ion current density by increasing theprobability of a channel comprising KCNQ2 being open, by decreasing theprobability of it being closed, by increasing conductance through thechannel, and/or increasing the number or expression of channels.

The activity of the compounds of the invention can also be representedby EC50. In some embodiments, the compounds of the invention have anEC50 in a potassium ion channel assay of from about 5 nM to about 10 μM.In other embodiments, the compounds have an EC50 from about 5 nM toabout 3 μM. In yet other embodiments, the compounds have an EC50 fromabout 5 nM to about 0.5 μM.

Changes in ion flux may be assessed by determining changes inpolarization (i.e., electrical potential) of the cell or membraneexpressing the potassium channel comprising, for example, KCNQ2, KCNQ2/3or the M-current. A preferred means to determine changes in cellularpolarization is by measuring changes in current or voltage with thevoltage-clamp and patch-clamp techniques, using the “cell-attached”mode, the “inside-out” mode, the “outside-out” mode, the “perforatedcell” mode, the “one or two electrode” mode, or the “whole cell” mode(see, e.g., Ackerman et al., New Engl. J. Med. 336:1575-1595 (1997)).Whole cell currents are conveniently determined using the standardmethodology (see, e.g., Hamil et al., Pflugers. Archiv. 391:85 (1981).Other known assays include: radiolabeled rubidium flux assays andfluorescence assays using voltage-sensitive dyes (see, e.g.,Vestergarrd-Bogind et al., J. Membrane Biol. 88:67-75 (1988); Daniel etal., J. Pharmacol. Meth. 25:185-193 (1991); Holevinsky et al., J.Membrane Biology 137:59-70 (1994)). Assays for compounds capable ofincreasing potassium flux through M-current channels found in nativecells or through the channel proteins comprising KCNQ2 orheteromultimers of KCNQ subunits can be performed by application of thecompounds to a bath solution in contact with and comprising cells havinga channel of interest (see, e.g., Blatz et al., Nature 323:718-720(1986); Park, J. Physiol. 481:555-570 (1994)). Generally, the compoundsto be tested are present in the range from 1 pM to 100 mM.

The effects of the test compounds upon the function of the channels canbe measured by changes in the electrical currents or ionic flux or bythe consequences of changes in currents and flux. Changes in electricalcurrent or ionic flux are measured by either increases or decreases influx of ions such as potassium or rubidium ions. The cations can bemeasured in a variety of standard ways. They can be measured directly byconcentration changes of the ions or indirectly by membrane potential orby radio-labeling of the ions. Consequences of the test compound on ionflux can be quite varied. Accordingly, any suitable physiological changecan be used to assess the influence of a test compound on the channelsof this invention. The effects of a test compound can be measured by atoxin binding assay. When the functional consequences are determinedusing intact cells or animals, one can also measure a variety of effectssuch as transmitter release (e.g., dopamine), hormone release (e.g.,insulin), transcriptional changes to both known and uncharacterizedgenetic markers (e.g., northern blots), cell volume changes (e.g., inred blood cells), immunoresponses (e.g., T cell activation), changes incell metabolism such as cell growth or pH changes, and changes inintracellular second messengers such as Ca²⁺, or cyclic nucleotides.

KCNQ2 orthologs will generally confer substantially similar propertieson a channel comprising such KCNQ2, as described above. In a preferredembodiment, the cell placed in contact with a compound that is suspectedto be a KCNQ2 homolog is assayed for increasing or decreasing ion fluxin a eukaryotic cell, e.g., an oocyte of Xenopus (e.g., Xenopus laevis)or a mammalian cell such as a CHO or HeLa cell. Channels that areaffected by compounds in ways similar to KCNQ2 are considered homologsor orthologs of KCNQ2.

Utilizing screening assays such as described above, compounds of theinvention were tested for their ability to open voltage-gated potassiumchannels. The results of these assays are set forth in Tables 1-5 inwhich the data are presented in terms of relative potency of thecompounds tested to one another. The compound numbers in Tables 1-5 arecross-referenced to the compounds displayed in Examples 1-5.

IV. Pharmaceutical Compositions of Potassium Channel Modulators

In another aspect, the present invention provides pharmaceuticalcompositions comprising/including a pharmaceutically acceptableexcipient and a compound described herein. In a group of exemplaryembodiments, the compounds have any of Formulas I, II, III, IV, V, VI,VII, VIII, IX, IXa, IXa-1, IXa-2, IXa-3, IXa-4, IXa-5, IXa-6, IXa-7,IXb-1, IXb-2, IXb-3, IXb-3, IXb-4, IXb-5, IXc, IXc-1 and IXc-2. Inanother embodiment, the present invention provides a pharmaceuticalcomposition comprising/including a compound set forth in Examples 1-5and Tables 1-5.

IVa. Formulation of the Compounds (Compositions)

The compounds of the present invention can be prepared and administeredin a wide variety of oral, parenteral and topical dosage forms. Thus,the compounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds described herein can be administered by inhalation, forexample, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. Accordingly, the presentinvention also provides pharmaceutical compositions comprising apharmaceutically acceptable carrier or excipient and a compounddescribed herein, or a pharmaceutically acceptable salt thereof. Thepresent invention also provides pharmaceutical compositions comprising apharmaceutically acceptable carrier or excipient and a compound ofFormulae I, II, III, IV, V, VI, VII, VIII, IX, IXa, IXa-1, IXa-2, IXa-3,IXa-4, IXa-5, IXa-6, IXa-7, IXb-1, IXb-2, IXb-3, IXb-3, IXb-4, IXb-5,IXc, IXc-1 and IXc-2, or a pharmaceutically acceptable salt thereof.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances, which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid, which is in a mixturewith the finely divided active component. In tablets, the activecomponent is mixed with the carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

The powders and tablets preferably contain from 5% or 10% to 70% of theactive compound. Suitable carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, a lowmelting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as a carrier providing a capsule in which theactive component with or without other carriers, is surrounded by acarrier, which is thus in association with it. Similarly, cachets andlozenges are included. Tablets, powders, capsules, pills, cachets, andlozenges can be used as solid dosage forms suitable for oraladministration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water/propylene glycol solutions. For parenteralinjection, liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizers, and thickening agents as desired. Aqueous suspensionssuitable for oral use can be made by dispersing the finely dividedactive component in water with viscous material, such as natural orsynthetic gums, resins, methylcellulose, sodium carboxymethylcellulose,and other well-known suspending agents.

Also included are solid form preparations, which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to1000 mg, most typically 10 mg to 500 mg, according to the particularapplication and the potency of the active component. The compositioncan, if desired, also contain other compatible therapeutic agents.

IVb. Effective Dosages

Pharmaceutical compositions provided by the present invention includecompositions wherein the active ingredient is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alia, on the condition beingtreated. For example, when administered in methods to treat pain oranxiety, such compositions will contain an amount of active ingredienteffective to achieve a clinically relevant degree of reduction in thecondition being treated. Similarly, when the pharmaceutical compositionis used to treat or prevent a central or peripheral nervous systemdisorder, e.g., Parkinson's disease a therapeutically effective amountwill reduce one or more symptoms characteristic of the diseases (e.g.,tremors) to below a predetermined pressure threshold. Determination of atherapeutically effective amount of a compound of the invention is wellwithin the capabilities of those skilled in the art, especially in lightof the detailed disclosure herein.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Target plasmaconcentrations will be those concentrations of active compound(s) thatare capable of modulating, e.g., activating or opening the KCNQ channel.In preferred embodiments, the KCNQ channel activity is altered by atleast 30%. Target plasma concentrations of active compound(s) that arecapable of inducing at least about 50%, 70%, or even 90% or higheralteration of the KCNQ channel potassium flux are presently preferred.The percentage of alteration of the KCNQ channel in the patient can bemonitored to assess the appropriateness of the plasma drug concentrationachieved, and the dosage can be adjusted upwards or downwards to achievethe desired percentage of alteration.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a circulating concentration thathas been found to be effective in animals. A particularly useful animalmodel for predicting anticonvulsant dosages is the maximal electroshockassay (Fischer RS, Brain Res. Rev. 14: 245-278 (1989)). The dosage inhumans can be adjusted by monitoring KCNQ channel activation andadjusting the dosage upwards or downwards, as described above.

A therapeutically effective dose can also be determined from human datafor compounds which are known to exhibit similar pharmacologicalactivities, such as retigabine (Rudnfeldt et al., Neuroscience Lett.282: 73-76 (2000)).

Adjusting the dose to achieve maximal efficacy in humans based on themethods described above and other methods as are well-known in the artis well within the capabilities of the ordinarily skilled artisan.

By way of example, when a compound of the invention is used in theprophylaxis and/or treatment of an exemplary disease such as epilepsy, acirculating concentration of administered compound of about 0.001 μM to20 μM is considered to be effective, with about 0.01 μM to 5 μM beingpreferred.

Patient doses for oral administration of the compounds described herein,which is the preferred mode of administration for prophylaxis and fortreatment of an exemplary disease such as epilepsy, typically range fromabout 1 mg/day to about 10,000 mg/day, more typically from about 10mg/day to about 1,000 mg/day, and most typically from about 1 mg/day toabout 500 mg/day. Stated in terms of patient body weight, typicaldosages range from about 0.01 to about 150 mg/kg/day, more typicallyfrom about 0.1 to about 15 mg/kg/day, and most typically from about 0.5to about 10 mg/kg/day.

For other modes of administration, dosage amount and interval can beadjusted individually to provide plasma levels of the administeredcompound effective for the particular clinical indication being treated.For example, if acute epileptic seizures are the most dominant clinicalmanifestation, in one embodiment, a compound according to the inventioncan be administered in relatively high concentrations multiple times perday. Alternatively, if the patient exhibits only periodic epilepticseizures on an infrequent, periodic or irregular basis, in oneembodiment, it may be more desirable to administer a compound of theinvention at minimal effective concentrations and to use a less frequentadministration regimen. This will provide a therapeutic regimen that iscommensurate with the severity of the individual's disease.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned which does not causesubstantial toxicity and yet is entirely effective to treat the clinicalsymptoms demonstrated by the particular patient. This planning shouldinvolve the careful choice of active compound by considering factorssuch as compound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration and the toxicity profile of the selected agent.

V. Methods for Increasing Ion Flow in Voltage-Dependent PotassiumChannels

In yet another aspect, the present invention provides methods forincreasing ion flow through voltage dependent potassium channels in acell. The method includes contacting a cell containing the target ionchannels with an amount of a compound of the invention as describedherein, sufficient to enhance the activity of a potassium channel. Inone embodiment, the method includes contacting a cell containing thetarget ion channels with a potassium channel modulating amount of acompound of any of Formulas I, II, III, IV, V, VI, VII, VIII, IX, IXa,IXa-1, IXa-2, IXa-3, IXa-4, IXa-5, IXa-6, IXa-7, IXb-1, IXb-2, IXb-3,IXb-3, IXb-4, IXb-5, IXc, IXc-1 and IXc-2. For instances, the compoundis present in an amount sufficient to enhance activities of a potassiumion channel.

The methods provided in this aspect of the invention are useful for thediagnosis of conditions that can be treated by modulating ion fluxthrough voltage-dependent potassium channels, or for determining if apatient will be responsive to therapeutic agents, which act by openingpotassium channels. In particular, a patient's cell sample can beobtained and contacted with a compound of the invention and the ion fluxcan be measured relative to a cell's ion flux in the absence of acompound of the invention, for example, a compound of any of Formulas I,II, III, IV, V, VI, VII, VIII, IX, IXa, IXa-1, IXa-2, IXa-3, IXa-4,IXa-5, IXa-6, IXa-7, IXb-1, IXb-2, IXb-3, IXb-3, IXb-4, IXb-5, IXc,IXc-1 and IXc-2 or a compound of any of sets 1-33. An increase in ionflux will typically indicate that the patient will be responsive to atherapeutic regimen of ion channel openers.

VI. Methods for Treating Conditions Mediated by Voltage-DependentPotassium Channels

The compounds of any of sets 1-33 described above or the compounds ofFormulas I, II, III, IV, V, VI, VII, VIII, IX, IXa, IXa-1, IXa-2, IXa-3,IXa-4, IXa-5, IXa-6, IXa-7, IXb-1, IXb-2, IXb-3, IXb-3, IXb-4, IXb-5,IXc, IXc-1 or IXc-2, or pharmaceutically acceptable salts, hydrates orsolvates thereof, which, inter alia, are useful in the treatment of arange of conditions, disorders and diseases through the modulation ofpotassium ion flux through voltage-dependent potassium channels. Moreparticularly, the invention provides compounds, compositions and methodsthat are useful in the treatment of central or peripheral nervous systemdisorders (e.g., migraine, ataxia, Parkinson's disease, bipolardisorders, trigeminal neuralgia, spasticity, mood disorders, braintumors, psychotic disorders, myokymia, seizures, epilepsy, hearing andvision loss, Alzheimer's disease, age-related memory loss, learningdeficiencies, anxiety and motor neuron diseases), and as neuroprotectiveagents (e.g., to prevent stroke and the like). Compounds of theinvention have use as agents for treating convulsive states, for examplethat following grand mal, petit mal, psychomotor epilepsy or focalseizure. The compounds of the invention are also useful in treatingdisease states such as gastroesophogeal reflux disorder andgastrointestinal hypomotility disorders.

The compounds of the invention are also useful in the treatment,prevention, inhibition and amelioration of urge urinary incontinencealso known as bladder instability, neurogenic bladder, voidingdysfunction, hyperactive bladder or detrusor overactivity. The methodsof this invention also include the prevention and treatment of mixedstress and urge urinary incontinence, including that associated withsecondary conditions such as prostate hypertrophy. The methods of thisinvention are useful for inducing, assisting or maintaining desirablebladder control in a mammal experiencing or susceptible to bladderinstability or urinary incontinence. These methods include prevention,treatment or inhibition of bladder-related urinary conditions andbladder instability, including idiopathic bladder instability, nocturnalenuresis, nocturia, voiding dysfunction and urinary incontinence. Alsotreatable or preventable with the methods of this invention is bladderinstability secondary to prostate hypertrophy. The compounds describedherein are also useful in promoting the temporary delay of urinationwhenever desirable. The compounds of this invention may also be utilizedto stabilize the bladder and treat or prevent incontinence which urgeurinary incontinence, stress urinary incontinence or a combination ofurge and stress incontinence in a mammal, which may also be referred toas mixed urge and stress incontinence. These methods include assistancein preventing or treating urinary incontinence associated with secondaryconditions such as prostate hypertrophy. These methods may be utilizedto allow a recipient to control the urgency and frequency of urination.The methods of this invention include the treatment, prevention,inhibition and amelioration of urge urinary incontinence also known asbladder instability, neurogenic bladder, voiding dysfunction,hyperactive bladder, detrusor overactivity, detrusor hyper-reflexia oruninhibited bladder.

As described above, methods of this invention include treatments,prevention, inhibition or amelioration of hyperactive or unstablebladder, neurogenic bladder, sensory bladder urgency, or hyperreflexicbladder. These uses include, but are not limited to, those for bladderactivities and instabilities in which the urinary urgency is associatedwith prostatitis, prostatic hypertrophy, interstitial cystitis, urinarytract infections or vaginitis. The methods of this invention may also beused to assist in inhibition or correction of the conditions ofFrequency-Urgency Syndrome, and lazy bladder, also known as infrequentvoiding syndrome. The methods of this invention may also be used totreat, prevent, inhibit, or limit the urinary incontinence, urinaryinstability or urinary urgency associated with or resulting fromadministrations of other medications, including diuretics, vasopressinantagonists, anticholinergic agents, sedatives or hypnotic agents,narcotics, alpha-adrenergic agonists, alpha-adrenergic antagonists, orcalcium channel blockers.

Moreover, compounds of the invention are useful in the treatment ofpain, for example, neuropathic pain, inflammatory pain, cancer pain,migraine pain, and musculoskeletal pain. The compounds are also usefulto treat conditions, which may themselves be the origin of pain, forexample, inflammatory conditions, including arthritic conditions (e.g.,rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and goutyarthritis) and non-articular inflammatory conditions (e.g., herniated,ruptured and prolapsed disc syndrome, bursitis, tendonitis,tenosynovitis, fibromyalgia syndrome, and other conditions associatedwith ligamentous sprain and regional musculoskeletal strain).Particularly preferred compounds of the invention are less ulcerogenicthan other anti-inflammatory agents (e.g., ibuprofen, naproxen andaspirin). Furthermore, the compounds of the invention are useful intreating conditions and pain associated with abnormally raised skeletalmuscle tone.

Physiological pain is an important protective mechanism designed to warnof danger from potentially injurious stimuli from the externalenvironment. The system operates through a specific set of primarysensory neurons and is activated by noxious stimuli via peripheraltransducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164for a review). These sensory fibers are known as nociceptors and arecharacteristically small diameter axons with slow conduction velocities.Nociceptors encode the intensity, duration and quality of noxiousstimulus and by virtue of their topographically organized projection tothe spinal cord, the location of the stimulus. The nociceptors are foundon nociceptive nerve fibers of which there are two main types, A-deltafibers (myelinated) and C fibers (non-myelinated). The activitygenerated by nociceptor input is transferred, after complex processingin the dorsal horn, either directly, or via brain stem relay nuclei, tothe ventrobasal thalamus and then on to the cortex, where the sensationof pain is generated.

Pain may generally be classified as acute or chronic. Acute pain beginssuddenly and is short-lived (usually twelve weeks or less). It isusually associated with a specific cause such as a specific injury andis often sharp and severe. It is the kind of pain that can occur afterspecific injuries resulting from surgery, dental work, a strain or asprain. Acute pain does not generally result in any persistentpsychological response. In contrast, chronic pain is long-term pain,typically persisting for more than three months and leading tosignificant psychological and emotional problems. Common examples ofchronic pain are neuropathic pain (e.g. painful diabetic neuropathy,post-herpetic neuralgia), carpal tunnel syndrome, back pain, headache,cancer pain, arthritic pain and chronic post-surgical pain.

When a substantial injury occurs to body tissue, via disease or trauma,the characteristics of nociceptor activation are altered and there issensitization in the periphery, locally around the injury and centrallywhere the nociceptors terminate. These effects lead to a heightenedsensation of pain. In acute pain these mechanisms can be useful, inpromoting protective behaviors which may better enable repair processesto take place. The normal expectation would be that sensitivity returnsto normal once the injury has healed. However, in many chronic painstates, the hypersensitivity far outlasts the healing process and isoften due to nervous system injury. This injury often leads toabnormalities in sensory nerve fibers associated with maladaptation andaberrant activity (Woolf& Salter, 2000, Science, 288, 1765-1768).

Clinical pain is present when discomfort and abnormal sensitivityfeature among the patient's symptoms. Patients tend to be quiteheterogeneous and may present with various pain symptoms. Such symptomsinclude: 1) spontaneous pain which may be dull, burning, or stabbing; 2)exaggerated pain responses to noxious stimuli (hyperalgesia); and 3)pain produced by normally innocuous stimuli (allodynia—Meyer et al.,1994, Textbook of Pain, 13-44). Although patients suffering from variousforms of acute and chronic pain may have similar symptoms, theunderlying mechanisms may be different and may, therefore, requiredifferent treatment strategies. Pain can also therefore be divided intoa number of different subtypes according to differing pathophysiology,including nociceptive, inflammatory and neuropathic pain.

Nociceptive pain is induced by tissue injury or by intense stimuli withthe potential to cause injury. Pain afferents are activated bytransduction of stimuli by nociceptors at the site of injury andactivate neurons in the spinal cord at the level of their termination.This is then relayed up the spinal tracts to the brain where pain isperceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activationof nociceptors activates two types of afferent nerve fibers. MyelinatedA-delta fibers transmit rapidly and are responsible for sharp andstabbing pain sensations, whilst unmyelinated C fibers transmit at aslower rate and convey a dull or aching pain. Moderate to severe acutenociceptive pain is a prominent feature of pain from central nervoussystem trauma, strains/sprains, burns, myocardial infarction and acutepancreatitis, post-operative pain (pain following any type of surgicalprocedure), posttraumatic pain, renal colic, cancer pain and back pain.Cancer pain may be chronic pain such as tumor related pain (e.g. bonepain, headache, facial pain or visceral pain) or pain associated withcancer therapy (e.g. postchemotherapy syndrome, chronic post-surgicalpain syndrome or post radiation syndrome). Cancer pain may also occur inresponse to chemotherapy, immunotherapy, hormonal therapy orradiotherapy. Back pain may be due to herniated or rupturedintervertabral discs or abnormalities of the lumber facet joints,sacroiliac joints, paraspinal muscles or the posterior longitudinalligament. Back pain may resolve naturally but in some patients, where itlasts over 12 weeks, it becomes a chronic condition which can beparticularly debilitating.

Neuropathic pain is currently defined as pain initiated or caused by aprimary lesion or dysfunction in the nervous system. Nerve damage can becaused by trauma and disease and thus the term ‘neuropathic pain’encompasses many disorders with diverse aetiologies. These include, butare not limited to, peripheral neuropathy, diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy,HIV neuropathy, phantom limb pain, carpal tunnel syndrome, centralpost-stroke pain and pain associated with chronic alcoholism,hypothyroidism, uremia, multiple sclerosis, spinal cord injury,Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic painis pathological as it has no protective role. It is often present wellafter the original cause has dissipated, commonly lasting for years,significantly decreasing a patient's quality of life (Woolf and Mannion,1999, Lancet, 353, 1959-1964). The symptoms of neuropathic pain aredifficult to treat, as they are often heterogeneous even betweenpatients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6,S141-S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). Theyinclude spontaneous pain, which can be continuous, and paroxysmal orabnormal evoked pain, such as hyperalgesia (increased sensitivity to anoxious stimulus) and allodynia (sensitivity to a normally innocuousstimulus).

The inflammatory process is a complex series of biochemical and cellularevents, activated in response to tissue injury or the presence offoreign substances, which results in swelling and pain (Levine andTaiwo, 1994, Textbook of Pain, 45-56). Arthritic pain is the most commoninflammatory pain. Rheumatoid disease is one of the commonest chronicinflammatory conditions in developed countries and rheumatoid arthritisis a common cause of disability. The exact aetiology of rheumatoidarthritis is unknown, but current hypotheses suggest that both geneticand microbiological factors may be important (Grennan & Jayson, 1994,Textbook of Pain, 397-407). It has been estimated that almost 16 millionAmericans have symptomatic osteoarthritis (OA) or degenerative jointdisease, most of whom are over 60 years of age, and this is expected toincrease to 40 million as the age of the population increases, makingthis a public health problem of enormous magnitude (Houge & Mersfelder,2002, Ann Pharmacother., 36, 679-686; McCarthy et al., 1994, Textbook ofPain, 387-395). Most patients with osteoarthritis seek medical attentionbecause of the associated pain. Arthritis has a significant impact onpsychosocial and physical function and is known to be the leading causeof disability in later life. Ankylosing spondylitis is also a rheumaticdisease that causes arthritis of the spine and sacroiliac joints. Itvaries from intermittent episodes of back pain that occur throughoutlife to a severe chronic disease that attacks the spine, peripheraljoints and other body organs.

Another type of inflammatory pain is visceral pain which includes painassociated with inflammatory bowel disease (IBD). Visceral pain is painassociated with the viscera, which encompass the organs of the abdominalcavity. These organs include the sex organs, spleen and part of thedigestive system. Pain associated with the viscera can be divided intodigestive visceral pain and non-digestive visceral pain. Commonlyencountered gastrointestinal (GI) disorders that cause pain includefunctional bowel disorder (FBD) and inflammatory bowel disease (IBD).These GI disorders include a wide range of disease states that arecurrently only moderately controlled, including, in respect of FBD,gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) andfunctional abdominal pain syndrome (FAPS), and, in respect of IBD,Crohn's disease, ileitis and ulcerative colitis, all of which regularlyproduce visceral pain. Other types of visceral pain include the painassociated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.

It should be noted that some types of pain have multiple aetiologies andthus can be classified in more than one area, e.g. back pain and cancerpain have both nociceptive and neuropathic components.

Other types of pain include:

-   -   pain resulting from musculo-skeletal disorders, including        myalgia, fibromyalgia, spondylitis, sero-negative        (non-rheumatoid) arthropathies, non-articular rheumatism,        dystrophinopathy, glycogenolysis, polymyositis and pyomyositis;    -   heart and vascular pain, including pain caused by angina,        myocardical infarction, mitral stenosis, pericarditis, Raynaud's        phenomenon, scleredoma and skeletal muscle ischemia;        head pain, such as migraine (including migraine with aura and        migraine without aura), cluster headache, tension-type headache        mixed headache and headache associated with vascular disorders;        and orofacial pain, including dental pain, otic pain, burning        mouth syndrome and temporomandibular myofascial pain.

The compounds of the invention are also of use in treating anxiety (e.g.anxiety disorders). Anxiety disorders are defined in the Diagnostic andStatistical Manual of Mental Disorders (Third Edition-revised 1987,published by the American Psychiatric Association, Washington, D.C.,see, pages 235 to 253), as psychiatric conditions having symptoms ofanxiety and avoidance behavior as characteristic features. Includedamongst such disorders are generalized anxiety disorder, simple phobiaand panic disorder.

Anxiety also occurs as a symptom associated with other psychiatricdisorders, for example, obsessive compulsive disorder, post-traumaticstress disorder, schizophrenia, mood disorders and major depressivedisorders, and with organic clinical conditions including, but notlimited to, Parkinson's disease, multiple sclerosis, and otherphysically incapacitating disorders.

In view of the above-noted discovery, the present invention providescompounds, compositions, and methods for increasing ion flux involtage-dependent potassium channels, particularly those channelsresponsible for the M-current. As used herein, the term “M-current,”“channels responsible for the M-current” and the like, refers to aslowly activating, non-inactivating, slowly deactivating voltage-gatedK⁺ channel. M-current is active at voltages close to the threshold foraction potential generation in a wide variety of neuronal cells, andthus, is an important regulator of neuronal excitability.

Recently, members of the voltage-dependent potassium channel family wereshown to be directly involved in diseases of the central or peripheralnervous system. The fused ring heterocycles provided herein are nowshown to act as potassium channel modulators.

In some embodiments, the present invention provides a method for thetreatment of a central or peripheral nervous system disorder orcondition through modulation of a voltage-dependent potassium channel.In this method, a subject in need of such treatment is administered aneffective amount of a compound having any of Formulas I, II, III, IV, V,VI, VII, VIII, IX, IXa, IXa-1, IXa-2, IXa-3, IXa-4, IXa-5, IXa-6, IXa-7,IXb-1, IXb-2, IXb-3, IXb-3, IXb-4, IXb-5, IXc, IXc-1 and IXc-2 or acompound of any of sets 1-33. In one embodiment, the present inventionprovides a method of treating, preventing, inhibiting or ameliorating acentral or peripheral nervous system disorder or condition throughmodulation of a potassium ion channel. The method includes administeringto a subject (i.e. a mammal or a human) in need of such treatment aneffective amount of a compound of any of Formulas IX, IXa, IXa-1, IXa-2,IXa-3, IXa-4, IXa-5, IXa-6, IXa-7, IXb-1, IXb-2, IXb-3, IXb-3, IXb-4,IXb-5, IXc, IXc-1 and IXc-2 or a compound of any of sets 1-33.

The compounds provided herein are useful as potassium channel modulatorsand find therapeutic utility via modulation of voltage-dependentpotassium channels in the treatment of diseases or conditions. Thepotassium channels targets for the compounds of the invention aredescribed herein as voltage-dependent potassium channels such as theKCNQ potassium channels. As noted above, these channels may includehomomultimers and heteromultimers of KCNQ2, KCNQ3, KCNQ4, KCNQ5 andKCNQ6. A heteromultimer of two proteins, e.g., KCNQ2 and KCNQ3 isreferred to as, for example, KCNQ2/3, KCNQ3/5, etc. The conditions thatcan be treated with the compounds and compositions of the presentinvention may include, but are not limited to, central or peripheralnervous system disorders (e.g., migraine, ataxia, Parkinson's disease,bipolar disorders, trigeminal neuralgia, spasticity, mood disorders,brain tumors, psychotic disorders, myokymia, seizures, epilepsy, hearingand vision loss, Alzheimer's disease, age-related memory loss, learningdeficiencies, anxiety, and motor neuron diseases). The compounds andcompositions of the present invention may also serve as neuroprotectiveagents (e.g., to prevent stroke and the like). In a preferredembodiment, the condition or disorder to be treated is epilepsy orseizures. In another preferred embodiment, the condition or disorder ishearing loss.

In therapeutic use for the treatment of epilepsy or other neurologicalconditions, the compounds utilized in the pharmaceutical method of theinvention are administered at the initial dosage of about 0.001 mg/kg toabout 1000 mg/kg daily. A daily dose range of about 0.1 mg/kg to about100 mg/kg is more typical. The dosages, however, may be varied dependingupon the requirements of the patient, the severity of the conditionbeing treated, and the compound being employed. Determination of theproper dosage for a particular situation is within the skill of thepractitioner. Generally, treatment is initiated with smaller dosages,which are less than the optimum dose of the compound. Thereafter, thedosage is increased by small increments until the optimum effect undercircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

In a group of embodiments, the present invention provides a compound asdescribed herein or a compound of any of sets 1-33 above, or apharmaceutically acceptable salt, hydrate or solvate thereof, for use asa medicament. In one embodiment, the compound has any of Formulas I, II,III, IV, V, VI, VII, VIII, IX, IXa, IXa-1, IXa-2, IXa-3, IXa-4, IXa-5,IXa-6, IXa-7, IXb-1, IXb-2, IXb-3, IXb-3, IXb-4, IXb-5, IXc, IXc-1 andIXc-2. In another embodiment, the compound has any of Formulas IX, IXa,IXa-1, IXa-2, IXa-3, IXa-4, IXa-5, IXa-6, IXa-7, IXb-1, IXb-2, IXb-3,IXb-3, IXb-4, IXb-5, IXc, IXc-1 and IXc-2.

In another group of embodiments, the present invention provides acompound as described herein or a compound of any of sets 1-33 above, ora pharmaceutically acceptable salt, hydrate or solvate thereof, for usein treating, preventing, inhibiting or ameliorating a central orperipheral nervous system disorder or condition. Exemplary disorders orconditions include migraine, ataxia, Parkinson's disease, bipolardisorders, trigeminal neuralgia, spasticity, mood disorders, braintumors, psychotic disorders, myokymia, seizures, epilepsy, stroke,hearing and vision loss, Alzheimer's disease, age-related memory loss,learning deficiencies, retinal degeneration, pain anxiety, neuronaldegeneration, motor neuron diseases and urinary incontinence. In oneembodiment, the compound has any of Formulas I, II, III, IV, V, VI, VII,VIII, IX, IXa, IXa-1, IXa-2, IXa-3, IXa-4, IXa-5, IXa-6, IXa-7, IXb-1,IXb-2, IXb-3, IXb-3, IXb-4, IXb-5, IXc, IXc-1 and IXc-2.

In yet another group of embodiments, the present invention provides acompound as described herein or a compound of any of sets 1-33 above, ora pharmaceutically acceptable salt, hydrate or solvate thereof, in themanufacture of a medicament for treating, preventing, inhibiting orameliorating a central or peripheral nervous system disorder orcondition. Exemplary disorders or conditions include migraine, ataxia,Parkinson's disease, bipolar disorders, trigeminal neuralgia,spasticity, mood disorders, brain tumors, psychotic disorders, myokymia,seizures, epilepsy, stroke, hearing and vision loss, Alzheimer'sdisease, age-related memory loss, learning deficiencies, retinaldegeneration, pain anxiety, neuronal degeneration, motor neuron diseasesand urinary incontinence. In one embodiment, the compound has any ofFormulas I, II, III, IV, V, VI, VII, VIII, IX, IXa, IXa-1, IXa-2, IXa-3,IXa-4, IXa-5, IXa-6, IXa-7, IXb-1, IXb-2, IXb-3, IXb-3, IXb-4, IXb-5,IXc, IXc-1 and IXc-2.

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Compounds within the scope of this invention can be synthesized asdescribed below, using a variety of reactions known to the skilledartisan. One skilled in the art will also recognize that alternativemethods may be employed to synthesize the target compounds of thisinvention, and that the approaches described within the body of thisdocument are not exhaustive, but do provide broadly applicable andpractical routes to compounds of interest.

Certain molecules claimed in this patent can exist in differentenantiomeric, diastereomeric and tautomeric forms and all such variantsof these compounds are claimed.

Those skilled in the art will also recognize that during standard workup procedures in organic chemistry, acids and bases are frequently used.Salts of the parent compounds are sometimes produced, if they possessthe necessary intrinsic acidity or basicity, during the experimentalprocedures described within this patent.

In the examples below, unless otherwise stated, temperatures are givenin degrees Celsius (° C.); operations were carried out at room orambient temperature (typically a range of from about 18-25° C.;evaporation of solvent was carried out using a rotary evaporator underreduced pressure (typically, 4.5-30 mmHg) with a bath temperature of upto 60° C.; the course of reactions was typically followed by TLC andreaction times are provided for illustration only; melting points areuncorrected; products exhibited satisfactory ¹H-NMR and/ormicroanalytical data; yields are provided for illustration only; and thefollowing conventional abbreviations are also used: mp (melting point),L (liter(s)), mL (milliliters), mmol (millimoles), g (grams), mg(milligrams), min (minutes), and h (hours).

The compounds were prepared using five related methods as described indetail below. Examples 1-5 illustrate each method along with thecompounds prepared using that method.

Example 1 Preparation ofN-(3-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide(g)

Synthesis of N-(5-Fluoro-pyridin-2-yl)-4-methyl-benzenesulfonamide (a):2-amino-5-fluoropyridine (25 g, 0.22 mol) in pyridine (100 mL) wastreated portion wise with p-toluenesulfonyl chloride (47.5 g, 0.25 mol)and heated at 80° C. for 2 hours. The cooled material was concentratedto remove the majority of pyridine. The resulting viscous solution wasdiluted with 200 ml of ethyl acetate then 200 ml of water. The resultingsuspension was stirred for about an hour to break up the solids thenfiltered. The filter cake was washed with water then cold ethyl acetate,dried to afford 59 g of a light brown solid. Rf 0.43, 50% ethylacetate/hexanes; MS m/z 266 (M+H).

Synthesis of 2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)acetamide (X:Sodium hydride (5.0 g, 0.21 mol) in N,N-Dimethylformamide (370 mL) wastreated portion wise withN-(5-Fluoro-pyridin-2-yl)-4-methyl-benzenesulfonamide (compound a, 50 g,0.2 mol). After stirring for 20 minutes, iodoacetamide (30 g, 0.2 mol)was added in one portion. The reaction stirred overnight at roomtemperature. The solvent was removed to give a brown solid. The crudematerial was diluted with 500 ml of ethyl acetate and 100 mL of waterand stirred for 2 hours. The solid was collected by filtration and driedto afford 36 g of 2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)acetamide.Rf 0.37, neat ethyl acetate MS m/z 324 (M+H).

Synthesis of2,2,2-trifluoro-N-(6-fluoroimidazo[1,2-a]pyridin-2-yl)acetamide (c):2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)acetamide (compound b, 36 g,0.11 mol) was taken up in 360 mL dichloromethane and treated with 135 mlof TFAA and stirred at room temperature for an hour. Solvent was removedand the residue taken up in ethyl acetate and sat. sodium bicarbonateand stirred until gas evolution ceased. The organic phase was separated,dried over sodium sulfate, filtered and concentrated to a light yellowsolid (33 g). The crude solid was purified by flash chromatography(0-100% ethyl acetate/hexane) to give 17 g of2,2,2-trifluoro-N-(6-fluoroimidazo[1,2-a]pyridin-2-yl)-acetamide. Rf0.39, 50% ethyl acetate/hexanes; MS m/z 248 (M+H).

Synthesis ofN-(3-Bromo-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide(d): N-Bromosuccinimide (2.96 g, 0.0166 mol) was added to a solution of2,2,2-Trifluoro-N-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-acetamide(compound c, 3.74 g, 0.0151 mol) in acetonitrile (70 mL) and stirred atroom temperature. The reaction mixture was stirred at room temperaturefor 15 minutes. Reaction mixture was concentrated under reducedpressure, crude product taken up in ethyl acetate, washed with water,organic layer collected, dried over Na2SO4, concentrated in vacuo andcrude product purified by column chromatography (50% ethylacetate/hexanes) to give product as an off white solid. Rf 0.47, 50%ethyl acetate/hexanes; MS m/z 327 (M+H).

Synthesis ofN-(3-cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide(e): Tetrakis(triphenylphosphine)palladium(0) (0.0797 g, 0.000069 mol)was added to a solution of 0.50 M of cyclopropylzinc bromide intetrahydrofuran (4.1 mL) andN-(3-bromo-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide(compound d, 0.225 g, 0.000690 mol) in tetrahydrofuran (20.0 mL) and thereaction was heated to reflux for 3 hours. An additional 0.50 M ofcyclopropylzinc bromide (4.1 mL) in tetrahydrofuran andtetrakis(triphenylphosphine)palladium(0)(0.080 g) was added and themixture was heated to reflux overnight. The reaction was concentrated invacuo and crude product purified by column chromatography (50% ethylacetate/hexanes) to giveN-(3-cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamideas a yellow solid. Rf 0.46, 50% ethyl acetate/hexanes; MS m/z 287 (M+H).

Synthesis of 3-Cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-ylamine (f):6.00 M of Sodium hydroxide in water (1.0 mL) was added to a solution ofN-(3-Cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoro-acetamide(compound e, 0.197 g, 0.000617 mol) in Methanol (2.00 mL, 0.0494 mol)and Tetrahydrofuran (2.0 mL, 0.0246 mol) and the reaction mixture wasstirred at 55° C. for 36 hours. The reaction mixture concentrated invacuo to dryness and crude product purified by column chromatography (5%methanol/dichloromethane) as a yellow solid. Rf 0.41, 5%methanol/dichloromethane; MS m/z 192 (M+H).

Synthesis ofN-(3-Cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-3,3-dimethyl-butyramide(g): Tert-butyl acetyl chloride (0.040 mL, 0.00029 mol) was added to asolution of 3-Cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-ylamine(compound f, 0.054 g, 0.00027 mol) in acetonitrile (5.00 mL) containingpyridine (0.0637 g, 0.00081 mol) and the mixture stirred at roomtemperature for 1 hour. The reaction mixture was concentrated in vacuoand crude product purified by column chromatography (50% ethylacetate/hexanes to neat ethyl acetate) to giveN-(3-cyclopropyl-6-fluoro-imidazo[1,2-a]pyridin-2-yl)-3,3-dimethyl-butyramideas a yellow solid. Rf 0.41, 5% methanol/dichloromethane; MS m/z 289(M+H). SH-SY5Y_EC50 (μM): 2.5464.

The following compounds were prepared according to the procedures ofMethod 1. In one embodiment, 2-aminopyridazine was used as the startingmaterial for the preparation of compounds 67, 68, 74, 76 and 78, whichcontain a imidazo[1,2-b]pyridazin moiety. The number next to eachcompound listed below corresponds to the compound number listed in Table1.

Following is a list of the compounds prepared by Method 1:

-   2,2,2-trifluoro-N-(5-methylimidazo[1,2-a]pyridin-2-yl)acetamide 8-   3,3-dimethyl-N-(5-methylimidazo[1,2-a]pyridin-2-yl)butanamide 9-   2,2,2-trifluoro-N-(6-fluoroimidazo[1,2-a]pyridin-2-yl)acetamide 10-   2,2,2-trifluoro-N-(6-fluoro-3-iodoimidazo[1,2-a]pyridin-2-yl)acetamide    111-   2,2,2-trifluoro-N-(5-(tri    fluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide 12-   2-(4-fluorophenyl)-N-(5-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    13-   N-(3-cyclopropyl-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    14-   N-(6-fluoro-3-neopentylimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    15-   N-(6-fluoro-3-(4-fluorobenzyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    16-   N-(6-fluoro-3-neopentylimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    17-   N-(6-fluoro-3-(4-fluorobenzyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    18-   3,3-dimethyl-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)butanamide    19-   N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    20-   2-(4-fluorophenyl)-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    21-   N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-phenoxyphenyl)acetamide    22-   4,4,4-trifluoro-3-methyl-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)butanamide    23-   4,4-dimethyl-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)pentanamide    24-   N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide    25-   N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-(trifluoromethoxy)phenyl)acetamide    26-   2-(4-chlorophenyl)-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    27-   N-(6-fluoro-3-(4-(trifluoromethyl)benzyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    28-   4,4,4-trifluoro-N-(6-fluoro-3-(4-(trifluoromethyl)benzyl)imidazo[1,2-a]pyridin-2-yl)-3-methylbutanamide    29-   N-(6-fluoro-3-(4-(trifluoromethyl)benzyl)imidazo[1,2-a]pyridin-2-yl)-2,3-dimethylbutanamide    30-   N-(3-isopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    31-   N-(3-(cyclohexylmethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    32-   N-(3-cyclohexyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    33-   2-(1-methylcyclopentyl)-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    34-   2-(3-chlorophenyl)-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    35-   N-(3-isopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    36-   N-(3-(cyclohexylmethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    37-   N-(3-cyclohexyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    38-   2-(4-fluorophenyl)-N-(3-isopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    39-   N-(3-(cyclohexylmethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    40-   N-(3-cyclohexyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    41-   2-(3-chlorophenyl)-N-(3-isopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    42-   2-(3-chlorophenyl)-N-(3-(cyclohexylmethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    43-   2-(3-chlorophenyl)-N-(3-cyclohexyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    44-   N-(3-isopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(1-methylcyclopentyl)acetamide    45-   N-(3-(cyclohexylmethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(1-methylcyclopentyl)acetamide    46-   N-(3-cyclohexyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(1-methylcyclopentyl)acetamide    47-   N-(3-cyclopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    48-   N-(3-cyclopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide-   N-(3-cyclopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    50-   N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)cyclopentanecarboxamide    51-   N-(3-(cyclohexylmethyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)cyclopentanecarboxamide    52-   N-(3-isopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)cyclopentanecarboxamide    53-   N-(3-cyclohexyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)cyclopentanecarboxamide    54-   N-(3-cyclopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)cyclopentanecarboxamide    55-   N-(3-cyclopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(1-methylcyclopentyl)acetamide    56-   2-cyclopropyl-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    57-   3-methyl-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)pentanamide    58-   N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)cyclohexanecarboxamide    59-   3,3,3-trifluoro-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)propanamide    60-   N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide    61-   N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    62-   3-methyl-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)butanamide    63-   N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide    64-   N-(3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    65-   N-(3-(cyclohexylmethyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    66-   3,3-dimethyl-N-(6-methyl-3-neopentylimidazo[1,2-b]pyridazin-2-yl)butanamide    67-   4,4,4-trifluoro-3-methyl-N-(6-methyl-3-neopentylimidazo[1,2-b]pyridazin-2-yl)butanamide    68-   N-(3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-4,4,4-trifluoro-3-methylbutanamide    69-   N-(3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    70-   2-(2,2-difluorocyclopentyl)-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    71-   2-cyclopentyl-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    72-   4,4-difluoro-N-(3-neopentyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)cyclohexanecarboxamide    73-   N-(3-cyclopropyl-6-methylimidazo[1,2-b]pyridazin-2-yl)-3,3-dimethylbutanamide    74-   N-(3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-4,4-difluorocyclohexanecarboxamide    75-   N-(3-cyclopropyl-6-methylimidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3-methylbutanamide    76-   N-(3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(3,4-difluorophenyl)acetamide    77-   N-(3-cyclopropyl-6-methylimidazo[1,2-b]pyridazin-2-yl)-4,4-difluorocyclohexanecarboxamide    78-   N-(3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(2,4-difluorophenyl)acetamide    79-   N-(3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(3,5-difluorophenyl)acetamide    80-   N-(3-cyclopropyl-5-methylimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    81-   3,3-dimethyl-N-(3-(thiazol-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)butanamide    82-   4,4,4-trifluoro-3-methyl-N-(3-(thiazol-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)butanamide    83-   2-(4-fluorophenyl)-N-(3-(thiazol-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    84-   N-(3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2,2-difluorocyclopropanecarboxamide    85-   4,4,4-trifluoro-3-methyl-N-(3-neopentylimidazo[1,2-a]pyridin-2-yl)butanamide    86-   4,4-difluoro-N-(3-neopentylimidazo[1,2-a]pyridin-2-yl)cyclohexanecarboxamide    87-   3,3-dimethyl-N-(3-neopentylimidazo[1,2-a]pyridin-2-yl)butanamide 88-   (R)—N-(3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-4,4,4-trifluoro-3-methylbutanamide    89-   (S)—N-(3-cyclopropyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-4,4,4-trifluoro-3-methylbutanamide    90

Table 1 sets forth potencies, purity, calculated molecular weights andmeasured molecular weights of representative compounds of the inventionin the SH-SY5Y native cell line in a FLIPR (Fluorometric Imaging PlateReader) assay, for a selection of compounds. The compound numbers inTable 1 correspond to the respective compound numbers listed above inExample 1.

TABLE 1 Compound SH-SY5Y Purity Molecular Observed m/z No. EC50, μM (%)Weight (M + H) 8 + 98 243.2 244.2 9 + 98 245.3 246.3 10 + 98 247.1 248.111 + 98 373.0 374.0 12 + 98 297.2 298.2 13 + 98 337.3 338.3 14 ++ 95289.3 290.3 15 ++ 95 319.4 320.4 16 +++ 95 357.4 358.4 17 +++ 95 357.4358.4 18 +++ 95 395.4 396.4 19 +++ 95 369.4 370.4 20 +++ 95 389.4 390.421 +++ 95 407.4 408.4 22 +++ 95 481.5 482.5 23 +++ 95 409.4 410.4 24 +++95 383.5 384.5 25 +++ 95 473.4 474.4 26 +++ 95 473.4 474.4 27 +++ 95423.9 424.9 28 +++ 95 407.4 408.4 29 +++ 90 447.3 448.3 30 ++ 100 407.4408.4 31 +++ 95 369.4 370.4 32 +++ 95 395.5 396.5 33 +++ 95 381.4 382.434 +++ 95 395.5 396.5 35 +++ 95 423.9 424.9 36 +++ 95 389.4 390.4 37 +++95 415.5 416.5 38 +++ 95 401.4 402.4 39 +++ 95 407.4 408.4 40 +++ 95433.4 434.4 41 +++ 95 419.4 420.4 42 +++ 95 423.9 424.9 43 +++ 95 449.9450.9 44 +++ 95 435.9 436.9 45 +++ 95 395.5 396.5 46 +++ 95 421.5 422.547 +++ 95 407.5 408.5 48 +++ 95 367.4 368.4 49 +++ 95 387.4 388.4 50 +++95 405.4 406.4 51 +++ 98 367.4 368.4 52 +++ 98 393.4 394.4 53 +++ 98367.4 368.4 54 +++ 98 379.4 380.4 55 +++ 98 365.4 366.4 56 +++ 95 393.4394.4 57 +++ 98 353.4 354.4 58 +++ 98 369.4 370.4 59 +++ 98 381.4 382.460 +++ 98 381.3 382.3 61 +++ 98 457.4 458.4 62 + 98 313.3 314.3 63 ++ 95355.4 356.4 64 ++ 98 339.4 340.4 65 ++ 95 339.4 340.4 66 +++ 95 345.5346.5 67 +++ 98 316.4 317.4 68 +++ 95 356.4 357.4 69 +++ 95 379.3 380.370 +++ 95 377.3 378.3 71 +++ 95 417.4 418.4 72 +++ 95 381.4 382.4 73 +++95 417.4 418.4 74 ++ 98 286.4 287.4 75 +++ 95 387.3 388.3 76 + 98 326.3327.3 77 +++ 95 395.3 396.3 78 ++ 98 334.4 335.4 79 ++ 95 395.3 396.3 80+++ 95 395.3 396.3 81 + 95 285.4 286.4 82 + 95 382.4 383.4 83 + 95 422.3423.3 84 +++ 95 420.4 421.4 85 ++ 95 345.3 346.3 86 ++ 98 341.4 342.4 87++ 98 349.4 350.4 88 ++ 95 301.4 302.4 89 ++ 95 379.3 380.3 90 ++ 95379.3 380.3 “+” represents 10 μM > EC₅₀ > 3 μM “++” represents 3 μM >EC₅₀ > 0.5 μM “+++” represents EC₅₀ < 0.5 μM

Example 2 Preparation ofN-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)-2-(4-fluoro-phenyl)acetamide(92)

Synthesis of 2-Bromo-2-phenylacetamide (h): Benzeneacetamide (3.0 g,0.022 mol) was dissolved in dichloromethane (60 mL) andN-bromosuccinimide (4.0 g, 0.022 mol) was added. The reaction wasstirred at room temperature under UV light for 24 hr. The mixture waspoured into water and the layers were separated. The organic layer waswashed with water (2×50 mL) then with brine (1×50 mL). The organic layerwas dried (magnesium sulfate) then chromatographed on silica (40% ethylacetate/hexanes) to give 2-Bromo-2-phenylacetamide, compound h Rf 0.37,40% ethyl acetate/hexanes; MS m/z 216 (M+H).

Synthesis of2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)-2-phenylacetamide (i):Sodium hydride (0.040 g, 0.0017 mol) was suspended inN,N-dimethylformamide (15 mL) and was cooled at 0° C.N-(5-fluoropyridin-2-yl)-4-methylbenzenesulfonamide (compound a, 0.37 g,0.0014 mol) was added and was stirred for 15 minutes.2-Bromo-2-phenylacetamide h (0.3 g, 0.001 mol) was added then thereaction was warmed to room temperature and was stirred for 24 hours.The reaction was poured into water and extracted with ethyl acetate(3×50 mL) then dried then chromatographed on silica (50% ethylacetate/hexanes) to give2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)-2-phenylacetamide (compoundj) Rf 0.42, 50% ethyl acetate/hexanes; MS m/z 400 (M+H).

Synthesis of2,2,2-trifluoro-N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)acetamide(k): 2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)-2-phenylacetamide(compound j, 0.370 g, 0.00093 mol) was dissolved in dichloromethane (5.0mL) and trifluoroacetic anhydride (2.0 mL, 0.014 mol) was added. Thereaction was stirred at room for 2 h. Solvent was removed and theresidue taken up in ethyl acetate then washed with saturated NaHCO₃(3×50 mL). Solvent removed to provide clean2,2,2-trifluoro-N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)acetamideRf 0.41, 70% ethyl acetate/hexanes; MS m/z 324 (M+H).

Synthesis of 6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-amine (l):2,2,2-trifluoro-N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)acetamide(compound k, 0.190 g, 0.0006 mol) was dissolved in methanol (8.0 mL) andwater (2 ml). To this was added potassium carbonate (0.2 g, 0.002 mol).The reaction was heated in the microwave at 100° C. for 45 min. Thesolvent concentrated and residue was partitioned between water (100 mL)and ethyl acetate (100 mL). The layers were separated and the organiclayer was dried (magnesium sulfate) then chromatographed on silica(55:40:5, DCM:acetonitrle:MeOH) to give6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-amine Rf 0.40, (55:40:5,DCM:acetonitrle:MeOH); MS m/z 228 (M+H).

Synthesis ofN-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide(92): 6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-amine (compound 1, 0.075g, 0.00033 mol) was dissolved in tetrahydrofuran (5.0 mL) and pyridine(29 uL, 0.00036 mol) was added. R×n cooled to 0° C. and4-fluorophenylacetyl chloride (48 uL, 0.00036 mol) was added. Thereaction was stirred at 0° C. for 30 minutes. The solvent was removedand the crude product was partioned between water (25 mL) and EtOAc (25mL). The layers were separated and the organic layer was washed 3×20 mLwith water. The organic layer was dried (magnesium sulfate) thenchromatographed on silica (70% ethyl acetate/hexanes) to giveN-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamideRf 0.37, 70% ethyl acetate/hexanes; MS m/z 364 (M+H). SH-SY5Y_EC50 (μM):0.7321.

The following compounds were prepared according to the procedures ofMethod 2. In one embodiment, 2-aminopyridazine was used as the startingmaterial in preparing compounds 271, 272, 305, 306, 308, 309, 316, 339and 346, which contain a imidazo[1,2-b]pyridazin moiety. In anotherembodiment, 2-aminopyrimidine was used as the starting material forpreparing compounds 317-325 and 329-333, which contain aimidazo[1,2-a]pyrimidin moiety. The number next to each compound listedbelow corresponds to the compound number in Table 2.

Following is a list of the compounds prepared by Method 2:

-   2,2,2-trifluoro-N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)acetamide    91-   N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    92-   N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    93-   2-cyclopentyl-N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)acetamide    94-   3,3,3-trifluoro-N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)propanamide    95-   N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide 96-   4,4,4-trifluoro-N-(6-fluoro-3-phenylimidazo[1,2-a]pyridin-2-yl)butanamide    97-   2-cyclopentyl-N-(3-phenyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    98-   2-(4-fluorophenyl)-N-(3-phenyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    99-   3,3-dimethyl-N-(3-phenyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)butanamide    100-   2-phenyl-N-(3-phenyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    101-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    102-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    103-   3,3,3-trifluoro-N-(3-phenyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)propanamide    104-   4,4,4-trifluoro-N-(3-phenyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)butanamide    105-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    106-   2-cyclopentyl-N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    107-   4,4,4-trifluoro-N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)butanamide    108-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylpropanamide    109-   2-phenyl-N-(3-phenyl-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)propanamide    110-   2-(4-fluorophenyl)-N-(3-(4-fluorophenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    111-   N-(3-(4-fluorophenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    112-   N-(3-(4-fluorophenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    113-   N-(3-(4-fluorophenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylpropanamide    114-   N-(3-(2,4-difluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    115-   N-(3-(2,4-difluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    116-   N-(3-(2,4-difluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    117-   2-cyclopentyl-N-(3-(2,4-difluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)acetamide    118-   N-(3-(4-fluorophenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    119-   N-(3-(4-fluorophenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    120-   2-(4-fluorophenyl)-N-(3-(4-fluorophenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    121-   N-(3-(2,4-difluorophenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    122-   N-(3-(2,4-difluorophenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    123-   N-(3-(2,4-difluorophenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    124-   2-cyclopentyl-N-(3-(2,4-difluorophenyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)acetamide    125-   N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    126-   N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    127-   N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    128-   2-cyclopropyl-N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    129-   N-(6-chloro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    130-   N-(6-chloro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    131-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-methoxyphenyl)acetamide    132-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-3-methylbutanamide    133-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-3-phenylpropanamide    134-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide    135-   2-(2,4-difluorophenyl)-N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    136-   2-(4-cyanophenyl)-N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    137-   2-(bicyclo[2.2.1]heptan-2-yl)-N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    138-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-3,5,5-trimethylhexanamide    139-   2-(2-chloro-4-fluorophenyl)-N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    140-   2-(2-chloro-6-fluorophenyl)-N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    141-   2-(3,4-dichlorophenyl)-N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    142-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-2-p-tolylacetamide    143-   4,4,4-trifluoro-N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-3-methylbutanamide    144-   2-(4-chlorophenyl)-N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    145-   benzyl    6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-ylcarbamate 146-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-3-methylpentanamide    147-   N-(3-(3-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    148-   N-(3-(3-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    149-   N-(3-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    150-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)hex-5-ynamide    151-   N-(6-bromo-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    152-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    153-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    154-   N-(3-(3-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    155-   2-cyclopentyl-N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    156-   2-cyclohexyl-N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    157-   N-(3-(2-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    158-   N-(6-cyano-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    159-   N-(6-cyano-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    160-   benzyl    6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-ylcarbamate    161-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-2,3-dimethylbutanamide-   N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    163-   N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    164-   N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    165-   N-(3-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    166-   N-(3-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    167-   N-(3-(4-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    168-   N-(3-(4-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    169-   2-cyclopentyl-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    170-   2-cyclopropyl-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    171-   3-cyclopropyl-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)propanamide    172-   4,4,4-trifluoro-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)butanamide    173-   5,5,5-trifluoro-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)pentanamide    174-   N-(3-(4-(2-cyanopropan-2-yl)phenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    175-   N-(3-(3-(2-cyanopropan-2-yl)phenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    176-   N-(3-(4-cyanophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    177-   3,3-dimethyl-N-(3-(4-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)butanamide    178-   N-(6-fluoro-3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-2-(1-methylcyclopentyl)acetamide    179-   N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(1-methylcyclopentyl)acetamide    180-   N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-hydroxy-3,3-dimethylbutanamide    181-   N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    182-   N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    183-   N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-2,3-dimethylbutanamide    184-   2-cyclobutyl-N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    185-   N-(3-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide    186-   N-(3-(4-fluorophenyl)-7-methylimidazo[1,2-a]pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide    187-   N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-4,4-dimethylpentanamide    188-   4-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-ylamino)-2,2-dimethyl-4-oxobutyl    acetate 189-   N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-4-hydroxy-3,3-dimethylbutanamide    190-   4-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-ylamino)-2,2-dimethyl-4-oxobutyl    acetate 191-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-4-hydroxy-3,3-dimethylbutanamide    192-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(1-methylcyclopentyl)acetamide    193-   2-cyclobutyl-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    194-   4,4,4-trifluoro-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-3-methylbutanamide    195-   N-(3-(3-(difluoromethyl)-4-fluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    196-   N-(3-(4-cyano-3-fluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    197-   N-(6-fluoro-3-(3-fluoro-5-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    198-   N-(6-fluoro-3-(3-fluoro-4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    199-   N-(6-fluoro-3-(4-methoxy-3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    200-   N-(6-fluoro-3-(3-fluoro-4-methylphenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    201-   2,2-difluoro-N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    202-   2-(4-fluorophenyl)-N-(3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    203-   2-(4-fluorophenyl)-N-(3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    204-   2-(4-fluorophenyl)-N-(3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    205-   2-tert-butoxy-N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    206-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    207-   2-tert-butoxy-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    208-   N-(3-(3,4-difluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-4,4,4-trifluoro-3-methylbutanamide    209-   N-(3-(3,4-difluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    210-   N-(3-(3,4-difluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    211-   N-(3-(3,4-difluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide-   1-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-3-(4-fluorophenethyl)urea    213-   1-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-3-(4-fluorobenzyl)urea    214-   1-tert-butyl-3-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)urea    215-   N-(6,7-dichloro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    216-   N-(6,7-dichloro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    217-   3-cyano-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-3-methylbutanamide    218-   N-(6,7-dichloro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-4,4,4-trifluoro-3-methylbutanamide    219-   3-cyclopentyl-N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)propanamide    220-   N-(3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    221-   2-cyclopentyl-N-(3-(4-fluorophenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    222-   3,3-dimethyl-N-(3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)butanamide-   2-cyclopentyl-N-(3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    224-   3,3-dimethyl-N-(3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)butanamide-   2-cyclopentyl-N-(3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    226-   N-(3-(3,5-difluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    227-   N-(3-(3,5-difluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    228-   N-(3-(3,5-difluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    229-   N-(3-(3,5-difluorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-4,4,4-trifluoro-3-methylbutanamide    230-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-phenoxyacetamide    231-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-phenoxypropanamide    232-   N-(6,7-dichloro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    233-   N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-2,3,3-trimethylbutanamide    234-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2,3,3-trimethylbutanamide    235-   N-(6,7-dichloro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    236-   2-(benzyloxy)-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    237-   2-(4-chlorophenyl)-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    238-   2-(3-chlorophenyl)-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    239-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(3-fluorophenyl)acetamide    240-   2-(3,4-difluorophenyl)-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    241-   2-(3,5-difluorophenyl)-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    242-   (R)—N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)tetrahydrofuran-2-carboxamide    243-   (S)—N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)tetrahydrofuran-2-carboxamide    244-   N-(7-methoxy-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    245-   N-(7-methoxy-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    246-   2-(2,4-dichlorophenoxy)-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    247-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)tetrahydrofuran-3-carboxamide    248-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2,3-dimethylbutanamide    249-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-3-(4-fluorophenoxy)propanamide    250-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)acetamide    251-   3,3,3-trifluoro-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)propanamide    252-   (R)—N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-methoxy-2-phenylacetamide    253-   (S)—N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-methoxy-2-phenylacetamide    254-   N-(6-fluoro-3-(4-fluoro-3-methylphenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    255-   N-(3-(2,4-difluoro-3-methylphenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    256-   N-(3-(4-chloro-3-methylphenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    257-   N-(3-(3-chloro-4-methylphenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    258-   N-(6-cyano-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    259-   N-(6-cyano-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    260-   3-tert-butoxy-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)propanamide    261-   N-(6,8-difluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    262-   3,3,3-trifluoro-N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)propanamide    263-   2-cyclopentyl-N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    264-   2-cyclopropyl-N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    265-   2-cyclobutyl-N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    266-   3,3,3-trifluoro-N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)propanamide    267-   2-cyclopentyl-N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    268-   2-cyclopropyl-N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    269-   2-cyclobutyl-N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    270-   N-(6-chloro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)-3,3-dimethylbutanamide    271-   N-(6-chloro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)-2-(4-fluorophenyl)acetamide    272-   N-(6-fluoro-3-p-tolylimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    273-   3-cyclopropyl-N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)propanamide    274-   4,4,4-trifluoro-N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)butanamide    275-   4,4,4-trifluoro-N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-3-methylbutanamide    276-   3-tert-butoxy-N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)propanamide    277-   N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2,3-dimethylbutanamide    278-   N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-4,4-dimethylpentanamide    279-   3-cyclopropyl-N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)propanamide    280-   4,4,4-trifluoro-N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)butanamide    281-   4,4,4-trifluoro-N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-3-methylbutanamide    282-   N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-4,4-dimethylpentanamide    283-   N-(3-(3-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3,3-trifluoropropanamide    284-   N-(3-(3-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-4,4,4-trifluorobutanamide    285-   N-(3-(3-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-(1-methylcyclopentyl)acetamide    286-   3-tert-butoxy-N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)propanamide    287-   N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-2,3-dimethylbutanamide    288-   N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopentanecarboxamide    289-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclopentanecarboxamide    290-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)cycloheptanecarboxamide    291-   N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2,3-dihydro-1H-indene-2-carboxamide    292-   N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)cycloheptanecarboxamide    293-   N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)cycloheptanecarboxamide    294-   N-(6-fluoro-3-(3-fluoro-4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-phenylacetamide    295-   N-(6-fluoro-3-(3-fluoro-4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    296-   N-(6-fluoro-3-(3-fluoro-4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide    297-   2-(3-chlorophenyl)-N-(6-fluoro-3-(3-fluoro-4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    298-   N-(3-(3-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-(4-(trifluoromethyl)phenyl)acetamide    299-   2-(3-chlorophenyl)-N-(3-(3-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)acetamide    300-   2-(4-chlorophenyl)-N-(3-(3-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)acetamide    301-   N-(3-(3-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-cyclopentylacetamide    302-   4,4,4-trifluoro-N-(6-fluoro-3-(3-fluoro-4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)butanamide    303-   N-(6-fluoro-3-(3-fluoro-4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-(1-methylcyclopentyl)acetamide    304-   3,3-dimethyl-N-(6-methyl-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-2-yl)butanamide    305-   2-(4-fluorophenyl)-N-(6-methyl-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide    306-   3,3,3-trifluoro-N-(7-methoxy-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)propanamide    307-   3,3-dimethyl-N-(6-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)butanamide    308-   2-(4-fluorophenyl)-N-(6-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide    309-   2-(4-chlorophenyl)-N-(6-fluoro-3-(3-fluoro-4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    310-   2-cyclopentyl-N-(6-fluoro-3-(3-fluoro-4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    311-   N-(6-fluoro-3-(3-fluoro-4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-2,3-dimethylbutanamide    312-   4,4,4-trifluoro-N-(6-fluoro-3-(3-fluoro-4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)-3-methylbutanamide    313-   N-(3-(3-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2,3-dimethylbutanamide    314-   N-(3-(3-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-4,4,4-trifluoro-3-methylbutanamide    315-   4,4,4-trifluoro-3-methyl-N-(6-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)butanamide    316-   N-(6-chloro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyrimidin-2-yl)-2-(4-fluorophenyl)acetamide    317-   N-(6-chloro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyrimidin-2-yl)-4,4,4-trifluoro-3-methylbutanamide    318-   N-(6-chloro-3-(3-chlorophenyl)imidazo[1,2-a]pyrimidin-2-yl)-3,3-dimethylbutanamide    319-   N-(6-chloro-3-(3-chlorophenyl)imidazo[1,2-a]pyrimidin-2-yl)-2-(4-fluorophenyl)acetamide    320-   N-(6-chloro-3-(3-chlorophenyl)imidazo[1,2-a]pyrimidin-2-yl)-4,4,4-trifluoro-3-methylbutanamide    321-   N-(6-chloro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyrimidin-2-yl)-3,3-dimethylbutanamide    322-   3,3-dimethyl-N-(3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyrimidin-2-yl)butanamide    323-   2-(4-fluorophenyl)-N-(3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyrimidin-2-yl)acetamide    324-   4,4,4-trifluoro-3-methyl-N-(3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyrimidin-2-yl)butanamide    325-   4,4-difluoro-N-(6-fluoro-3-(4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclohexanecarboxamide    326-   4,4-difluoro-N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclohexanecarboxamide    327-   4,4-difluoro-N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclohexanecarboxamide    328-   N-(3-(3-chlorophenyl)imidazo[1,2-a]pyrimidin-2-yl)-3,3-dimethylbutanamide    329-   N-(3-(3-chlorophenyl)imidazo[1,2-a]pyrimidin-2-yl)-2-(4-fluorophenyl)acetamide    330-   N-(3-(3-chlorophenyl)imidazo[1,2-a]pyrimidin-2-yl)-4,4,4-trifluoro-3-methylbutanamide    331-   N-(6-fluoro-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyrimidin-2-yl)-3,3-dimethylbutanamide    332-   N-(6-fluoro-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyrimidin-2-yl)-3,3-dimethylbutanamide    333-   N-(6-fluoro-3-(3-fluoro-4-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)cyclobutanecarboxamide    334-   N-(3-(3-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)cyclobutanecarboxamide-   3,3-dimethyl-N-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)butanamide    336-   4,4,4-trifluoro-3-methyl-N-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)butanamide    337-   2-(4-fluorophenyl)-N-(3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    338-   N-(6-methoxy-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-b]pyridazin-2-yl)-3,3-dimethylbutanamide    339-   (S)-1-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-ylamino)-3,3-dimethyl-1-oxobutan-2-yl    acetate 340-   (S)—N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)-2-hydroxy-3,3-dimethylbutanamide    341-   3,3-dimethyl-N-(3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)butanamide    342-   4,4,4-trifluoro-3-methyl-N-(3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)butanamide    343-   2-(4-fluorophenyl)-N-(3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-a]pyridin-2-yl)acetamide    344-   4,4-difluoro-N-(6-fluoro-3-(4-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxamide    345-   N-(6-methoxy-3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-2-yl)-3,3-dimethylbutanamide    346

Table 2 sets forth potencies, purity, calculated molecular weights andmeasured molecular weights of representative compounds of the inventionin the SH-SY5Y native cell line in a FLIPR assay, for a selection ofcompounds. The compound numbers in Table 2 correspond to the respectivecompound numbers listed above in Example 2.

TABLE 2 Compound SH-SY5Y Purity Molecular Observed m/z No. EC50, μM (%)Weight (M + H) 91 + 98 323.2 324.2 92 ++ 98 363.4 364.4 93 ++ 98 325.4326.4 94 +++ 98 337.4 338.4 95 + 98 337.3 338.3 96 ++ 98 345.4 346.4 97++ 98 351.3 352.3 98 ++ 98 387.4 388.4 99 +++ 98 413.4 414.4 100 ++ 98375.4 376.4 101 ++ 98 395.4 396.4 102 +++ 98 381.4 382.4 103 +++ 98343.4 344.4 104 + 98 387.3 388.3 105 + 98 401.3 402.3 106 ++ 95 363.4364.4 107 +++ 99 355.4 356.4 108 ++ 99 369.3 370.3 109 ++ 99 377.4 378.4110 ++ 98 409.4 410.4 111 ++ 98 431.4 432.4 112 ++ 95 413.4 414.4 113 ++95 393.4 394.4 114 ++ 97 427.4 428.4 115 ++ 98 381.4 382.4 116 ++ 98361.4 362.4 117 ++ 98 399.3 400.3 118 ++ 98 373.4 374.4 119 +++ 98 413.4414.4 120 +++ 98 393.4 394.4 121 +++ 98 431.4 432.4 122 ++ 98 449.3450.3 123 ++ 98 411.4 412.4 124 ++ 98 431.4 432.4 125 ++ 98 423.4 424.4126 ++ 98 431.4 432.4 127 +++ 98 413.4 414.4 128 +++ 98 393.4 394.4129 + 98 327.3 328.3 130 +++ 98 359.8 360.8 131 +++ 98 397.8 398.8 132++ 96 393.4 394.4 133 ++ 95 329.3 330.3 134 ++ 96 377.4 378.4 135 ++ 98431.4 432.4 136 ++ 98 399.3 400.3 137 ++ 98 388.4 389.4 138 +++ 98 381.4382.4 139 +++ 98 385.5 386.5 140 + 98 415.8 416.8 141 + 98 415.8 416.8142 +++ 98 432.3 433.3 143 +++ 98 377.4 378.4 144 ++ 98 383.3 384.3 145++ 98 397.8 398.8 146 +++ 97 379.4 380.4 147 ++ 95 343.4 344.4 148 +++99 397.8 398.8 149 +++ 99 359.8 360.8 150 +++ 99 359.8 360.8 151 ++ 98339.3 340.3 152 +++ 98 404.3 405.3 153 +++ 99 409.4 410.4 154 +++ 99447.4 448.4 155 +++ 99 379.8 380.8 156 +++ 98 405.4 406.4 157 +++ 98419.4 420.4 158 ++ 99 359.8 360.8 159 ++ 98 350.4 351.4 160 ++ 98 370.4371.4 161 + 98 429.4 430.4 162 ++ 98 343.4 344.4 163 +++ 99 393.4 394.4164 +++ 99 431.4 432.4 165 +++ 98 413.4 414.4 166 +++ 98 359.4 360.4 167+++ 98 339.4 340.4 168 +++ 98 359.4 360.4 169 +++ 98 339.4 340.4 170 +++95 421.4 422.4 171 ++ 99 393.3 394.3 172 ++ 99 407.4 408.4 173 ++ 99435.3 436.3 174 +++ 99 449.3 450.3 175 ++ 98 392.5 393.5 176 ++ 98 392.5393.5 177 ++ 99 350.4 351.4 178 +++ 98 459.4 460.4 179 +++ 98 369.4370.4 180 +++ 98 419.4 420.4 181 ++ 95 409.4 410.4 182 +++ 99 409.4410.4 183 +++ 99 447.4 448.4 184 ++ 98 393.4 394.4 185 +++ 98 391.4392.4 186 +++ 98 427.4 428.4 187 +++ 98 427.4 428.4 188 +++ 95 407.4408.4 189 + 95 451.4 452.4 190 + 95 409.4 410.4 191 + 95 467.4 468.4 192++ 95 425.4 426.4 193 +++ 98 435.4 436.4 194 +++ 98 407.4 408.4 195 +++99 449.3 450.3 196 +++ 96 393.4 394.4 197 ++ 97 368.4 369.4 198 +++ 99411.4 412.4 199 +++ 99 411.4 412.4 200 +++ 98 423.4 424.4 201 +++ 97357.4 358.4 202 +++ 95 429.4 430.4 203 ++ 98 363.4 364.4 204 +++ 98413.4 414.4 205 +++ 97 429.4 430.4 206 + 98 409.4 410.4 207 +++ 99 429.4430.4 208 + 99 425.4 426.4 209 +++ 99 401.3 402.3 210 +++ 99 399.3 400.3211 +++ 99 381.4 382.4 212 +++ 99 361.4 362.4 213 + 95 460.4 461.4 214++ 94 446.4 447.4 215 ++ 95 394.4 395.4 216 +++ 98 460.3 461.3 217 ++ 98498.3 499.3 218 ++ 98 420.4 421.4 219 ++ 95 500.2 501.2 220 +++ 98 419.4420.4 221 ++ 99 325.4 326.4 222 ++ 99 337.4 338.4 223 +++ 99 375.4 376.4224 +++ 99 387.4 388.4 225 +++ 99 391.4 392.4 226 +++ 99 403.4 404.4 227+++ 99 361.4 362.4 228 +++ 99 381.4 382.4 229 +++ 99 399.3 400.3 230 ++99 401.3 402.3 231 + 99 445.4 446.4 232 + 99 459.4 460.4 233 +++ 95444.3 445.3 234 +++ 98 407.4 408.4 235 +++ 98 423.4 424.4 236 +++ 98482.3 483.3 237 + 99 459.4 460.4 238 +++ 99 463.8 464.8 239 +++ 99 463.8464.8 240 +++ 98 447.4 448.4 241 +++ 99 465.3 466.3 242 +++ 99 465.3466.3 243 + 99 409.3 410.3 244 + 99 409.3 410.3 245 ++ 98 405.4 406.4246 ++ 95 425.4 426.4 247 + 99 514.3 515.3 248 + 99 409.3 410.3 249 +++99 409.4 410.4 250 ++ 99 477.4 478.4 251 ++ 99 437.4 438.4 252 +++ 99421.3 422.3 253 + 99 459.4 460.4 254 + 99 459.4 460.4 255 +++ 96 357.4358.4 256 ++ 98 375.4 376.4 257 +++ 97 373.9 374.9 258 +++ 97 373.9374.9 259 +++ 98 400.4 401.4 260 +++ 98 438.4 439.4 261 +++ 99 439.4440.4 262 +++ 97 427.4 428.4 263 ++ 99 421.3 422.3 264 +++ 99 421.4422.4 265 ++ 99 393.3 394.3 266 +++ 99 407.4 408.4 267 ++ 99 405.3 406.3268 +++ 99 405.4 406.4 269 ++ 99 377.3 378.3 270 +++ 99 391.4 392.4 271+++ 98 410.8 411.8 272 ++ 98 448.8 449.8 273 ++ 97 339.4 340.4 274 +++99 407.4 408.4 275 ++ 99 435.3 436.3 276 +++ 99 449.3 450.3 277 +++ 98439.4 440.4 278 +++ 99 409.4 410.4 279 +++ 99 423.4 424.4 280 ++ 99391.4 392.4 281 ++ 99 419.3 420.3 282 +++ 99 433.3 434.3 283 +++ 99407.4 408.4 284 ++ 98 371.7 372.7 285 ++ 98 385.7 386.7 286 +++ 98 385.9386.9 287 ++ 98 423.4 424.4 288 ++ 98 393.4 394.4 289 +++ 99 391.4 392.4290 +++ 99 407.4 408.4 291 +++ 99 435.4 436.4 292 ++ 99 455.4 456.4 293+++ 99 435.4 436.4 294 +++ 99 419.4 420.4 295 +++ 99 447.4 448.4 296 +++99 465.3 466.3 297 +++ 99 515.4 516.4 298 +++ 99 481.8 482.8 299 ++ 99447.8 448.8 300 +++ 99 414.3 415.3 301 +++ 98 414.3 415.3 302 +++ 99371.8 372.8 303 ++ 98 453.3 454.3 304 +++ 98 453.4 454.4 305 +++ 98406.4 407.4 306 +++ 98 444.4 445.4 307 + 98 417.3 418.3 308 +++ 98 390.4391.4 309 +++ 98 428.4 429.4 310 +++ 99 481.8 482.8 311 +++ 99 439.4440.4 312 +++ 99 427.4 428.4 313 +++ 99 467.3 468.3 314 +++ 99 359.8360.8 315 ++ 99 399.8 400.8 316 +++ 98 430.3 431.3 317 ++ 95 448.8 449.8318 ++ 96 450.8 451.8 319 + 95 377.3 378.3 320 + 99 415.2 416.2 321 + 99417.2 418.2 322 + 99 410.8 411.8 323 + 97 392.4 393.4 324 + 99 430.4431.4 325 + 99 432.3 433.3 326 +++ 97 457.4 458.4 327 +++ 99 457.4 458.4328 +++ 99 441.4 442.4 329 + 96 342.8 343.8 330 + 96 380.8 381.8 331 +98 382.8 383.8 332 + 98 394.4 395.4 333 ++ 98 410.4 411.4 334 ++ 98411.3 412.3 335 ++ 98 343.8 344.8 336 ++ 98 375.4 376.4 337 ++ 98 415.3416.3 338 ++ 98 413.4 414.4 339 ++ 98 406.4 407.4 340 + 95 451.4 452.4341 ++ 95 409.4 410.4 342 +++ 98 391.4 392.4 343 ++ 98 431.3 432.3 344+++ 98 429.4 430.4 345 ++ 95 442.4 443.4 346 +++ 97 422.4 423.4 “+”represents 10 μM > EC₅₀ > 3 μM “++” represents 3 μM > EC₅₀ > 0.5 μM“+++” represents EC₅₀ < 0.5 μM

Example 3 Preparation ofN-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3,3-trifluoropropanamide(381)

Synthesis of3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-amine (m):2,2,2-Trifluoro-N-(6-fluoro-imidazo[1,2-a]pyridin-2-yl)-acetamide(compound c, 6 g, 0.02 mol), 2-bromo-1,3-benzothiazole (6.8 g, 32 mmol),potassium carbonate (7000 mg, 0.05 mol), and triphenylphosphine (1000mg, 0.005 mol) were diluted with 60 ml of a 2:1 solution ofdioxane/ethanol and treated with palladium acetate (500 mg, 0.002 mol).The reaction was heated at 100° C. overnight. The reaction was cooledand resulting solid was filtered and washed with dichloromethane thendried to give3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-amine as ayellow solid. Rf 0.37, 70% ethyl acetate/hexanes; MS m/z 285 (M+H).

Synthesis ofN-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3,3-trifluoropropanamide(381): 3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-amine(compound m, 250 mg, 0.0009 mol) in pyridine (0.2 mL) was treated with3,3,3-trifluoropropionyl chloride (0.134 mL, 0.0011 mol) and shaken atroom temperature for about 45 min. The solvent was removed and the crudeproduct was purified by column chromatography (50% ethyl acetate/hexane)to giveN-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3,3-trifluoropropanamideas a white solid. Rf 0.32, 70% ethyl acetate/hexanes; MS m/z 395 (M+H).SH-SY5Y_EC50 (μM): 2.1258.

The following compounds were prepared according to the procedures ofMethod 3. In one embodiment, 2-aminopyridazine was used as the startingmaterial in preparing compounds 382, 385-390, 394-397 and 415, whichcontain a imidazo[1,2-b]pyridazin moiety. In another embodiment,2-aminopyrimidine was used as the starting material for preparingcompounds 362 and 377, which contain a imidazo[1,2-a]pyrimidin moiety,The number next to each compound listed below corresponds to thecompound number in Table 3.

Following is a list of the compounds prepared by Method 3:

-   N-(6-fluoro-3-(pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    347-   N-(6-fluoro-3-(pyridin-3-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    348-   N-(6-fluoro-3-(6-fluoropyridin-3-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    349-   N-(3-(6-cyanopyridin-3-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    350-   N-(6-fluoro-3-(pyridin-4-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    351-   N-(6-fluoro-3-(5-fluoropyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    352-   N-(6-fluoro-3-(5-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    353-   N-(3-(5-cyanopyridin-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    354-   N-(6-fluoro-3-(5-(trifluoromethyl)pyridin-3-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    355-   N-(3,3-dimethylbutanoyl)-N-(6-fluoro-3-(5-methylpyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    356-   N-(3,3-dimethylbutanoyl)-N-(6-fluoro-3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    357-   N-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-N-(3,3-dimethylbutanoyl)-3,3-dimethylbutanamide    358-   N-(6-fluoro-3-(5-methylpyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    359-   N-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    360-   N-(6-fluoro-3-(6-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    361-   N-(6-fluoro-3-(pyrimidin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    362-   N-(3-(5-chloropyridin-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    363-   N-(3-(4-chloropyridin-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    364-   N-(6-fluoro-3-(4-methylpyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    365-   N-(6-fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    366-   N-(6-fluoro-3-(6-methoxypyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    367-   N-(6-fluoro-3-(5-fluoropyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-2,3-dimethylbutanamide    368-   4,4,4-trifluoro-N-(6-fluoro-3-(5-fluoropyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3-methylbutanamide    369-   N-(6-fluoro-3-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    370-   N-(6-fluoro-3-(thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    371-   N-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-4,4-dimethylpentanamide    372-   N-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2,3-dimethylbutanamide    373-   N-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-4,4,4-trifluoro-3-methylbutanamide    374-   N-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-(1-methylcyclopentyl)acetamide    375-   N-(3-(benzo[d]thiazol-2-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    376-   N-(6-fluoro-3-(4-(trifluoromethyl)pyrimidin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    377-   N-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)cyclopentanecarboxamide    378-   N-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    379-   N-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-2-cyclopentylacetamide    380-   N-(3-(benzo[d]thiazol-2-yl)-6-fluoroimidazo[1,2-a]pyridin-2-yl)-3,3,3-trifluoropropanamide    381-   N-(3-(benzo[d]thiazol-2-yl)-6-methylimidazo[1,2-b]pyridazin-2-yl)-3,3-dimethylbutanamide    382-   4,4,4-trifluoro-N-(6-fluoro-3-(thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)-3-methylbutanamide    383-   N-(6-fluoro-3-(thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    384-   N-(3-(benzo[d]thiazol-2-yl)-6-methylimidazo[1,2-b]pyridazin-2-yl)-2-(4-fluorophenyl)acetamide    385-   N-(3-(benzo[d]thiazol-2-yl)-6-methylimidazo[1,2-b]pyridazin-2-yl)-4,4,4-trifluoro-3-methylbutanamide    386-   3,3-dimethyl-N-(6-methyl-3-(thiazol-2-yl)imidazo[1,2-b]pyridazin-2-yl)butanamide    387-   4,4,4-trifluoro-3-methyl-N-(6-methyl-3-(thiazol-2-yl)imidazo[1,2-b]pyridazin-2-yl)butanamide    388-   4,4-difluoro-N-(6-methyl-3-(thiazol-2-yl)imidazo[1,2-b]pyridazin-2-yl)cyclohexanecarboxamide    389-   2-(4-fluorophenyl)-N-(6-methyl-3-(thiazol-2-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide    390-   4,4-difluoro-N-(6-fluoro-3-(thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)cyclohexanecarboxamide    391-   N-(3-(benzo[d]thiazol-2-yl)-5-methylimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    392-   N-(3-(benzo[d]thiazol-2-yl)-5-methylimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    393-   3,3-dimethyl-N-(6-methyl-3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-2-yl)butanamide    394-   2-(4-fluorophenyl)-N-(6-methyl-3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide    395-   4,4,4-trifluoro-3-methyl-N-(6-methyl-3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-2-yl)butanamide    396-   4,4-difluoro-N-(6-methyl-3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-b]pyridazin-2-yl)cyclohexanecarboxamide    397-   3,3-dimethyl-N-(6-(trifluoromethyl)-3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)butanamide    398-   4,4,4-trifluoro-3-methyl-N-(6-(trifluoromethyl)-3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)butanamide    399-   2-(4-fluorophenyl)-N-(6-(trifluoromethyl)-3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)acetamide    400-   4,4,4-trifluoro-N-(6-fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-3-methylbutanamide    401-   4,4-difluoro-N-(6-fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)cyclohexanecarboxamide    402-   2-(4-fluorophenyl)-N-(3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)acetamide    403-   3,3-dimethyl-N-(3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)butanamide    404-   4,4,4-trifluoro-3-methyl-N-(3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)butanamide    405-   3,3-dimethyl-N-(3-(thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)butanamide    406-   2-(4-fluorophenyl)-N-(3-(thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)acetamide    407-   4,4,4-trifluoro-3-methyl-N-(3-(thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)butanamide    408-   4,4-difluoro-N-(3-(thiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)cyclohexanecarboxamide    409-   N-(6-fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    410-   4,4-difluoro-N-(3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)cyclohexanecarboxamide    411-   2,2-difluoro-N-(6-fluoro-3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide    412-   2,2-difluoro-N-(3-(4-(trifluoromethyl)pyridin-2-yl)imidazo[1,2-a]pyridin-2-yl)cyclopropanecarboxamide    413-   3,3-dimethyl-N-(3-(thiazol-4-yl)imidazo[1,2-a]pyridin-2-yl)butanamide    414-   N-(6-methoxy-3-(thiazol-2-yl)imidazo[1,2-b]pyridazin-2-yl)-3,3-dimethylbutanamide    415-   3,3-dimethyl-N-(3-(2-methylthiazol-4-yl)imidazo[1,2-a]pyridin-2-yl)butanamide    416-   3,3-dimethyl-N-(3-(5-methylthiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)butanamide    417-   4,4,4-trifluoro-3-methyl-N-(3-(5-methylthiazol-2-yl)imidazo[1,2-a]pyridin-2-yl)butanamide    418

Table 3 sets forth potencies, purity, calculated molecular weights andmeasured molecular weights of representative compounds of the inventionin the SH-SY5Y native cell line in a FLIPR assay, for a selection ofcompounds. The compound numbers in Table 3 correspond to the compoundnumbers following each compound listed above in Example 3.

TABLE 3 Compound SH-SY5Y Purity Molecular Observed m/z No. EC50, μM (%)Weight (M + H) 347 + 90 326.4 327.4 348 + 95 326.4 327.4 349 ++ 90 344.4345.4 350 ++ 90 351.4 352.4 351 + 90 326.4 327.4 352 ++ 90 344.4 345.4353 +++ 90 394.4 395.4 354 + 95 351.4 352.4 355 + 100 394.4 395.4 356 +90 438.5 439.5 357 + 100 492.5 493.5 358 + 90 480.6 481.6 359 ++ 95340.4 341.4 360 +++ 90 382.5 383.5 361 +++ 100 394.4 395.4 362 + 90327.4 328.4 363 +++ 97 360.8 361.8 364 ++ 99 360.8 361.8 365 ++ 99 340.4341.4 366 +++ 99 394.4 395.4 367 ++ 100 356.4 357.4 368 + 100 344.4345.4 369 + 100 384.3 385.3 370 + 100 357.4 358.4 371 ++ 90 332.4 333.4372 ++ 95 396.5 397.5 373 + 95 382.5 383.5 374 + 90 422.4 423.4 375 +++100 408.5 409.5 376 +++ 100 432.5 433.5 377 + 98 395.4 396.4 378 + 95380.4 381.4 379 ++ 90 420.4 421.4 380 ++ 90 394.5 395.5 381 ++ 95 394.3395.3 382 + 98 379.5 380.5 383 + 98 372.3 373.3 384 ++ 92 370.4 371.4385 + 98 417.5 418.5 386 + 98 419.4 420.4 387 + 95 329.4 330.4 388 + 95369.4 370.4 389 + 95 377.4 378.4 390 + 95 367.4 368.4 391 +++ 95 380.4381.4 392 + 98 378.5 379.5 393 ++ 98 416.5 417.5 394 + 95 391.4 392.4395 + 95 429.4 430.4 396 + 95 431.3 432.3 397 + 95 439.4 440.4 398 +++95 444.4 445.4 399 ++ 95 484.3 485.3 400 +++ 95 482.4 483.4 401 ++ 95434.3 435.3 402 +++ 95 442.4 443.4 403 +++ 95 414.4 415.4 404 ++ 95376.4 377.4 405 ++ 98 416.3 417.3 406 ++ 95 314.4 315.4 407 ++ 95 352.4353.4 408 + 95 354.4 355.4 409 ++ 95 362.4 363.4 410 +++ 95 432.3 433.3411 +++ 90 424.4 425.4 412 + 90 400.3 401.3 413 ++ 98 382.3 383.3 414 +98 314.4 315.4 415 + 97 345.4 346.4 416 + 98 328.4 329.4 417 98 328.4329.4 418 98 368.4 369.4 “+” represents 10 μM > EC₅₀ > 3 μM “++”represents 3 μM > EC₅₀ > 0.5 μM “+++” represents EC₅₀ < 0.5 μM

Example 4 5 Preparation of3,3-Dimethyl-N-[5-methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-yl]-butyramide(419)

Synthesis of 5-Methylimidazo[1,2-a]pyridine-2-carboxylic acid ethylester (n): 2-Amino-6-methylpyridine (5 g, 0.05 mol) was dissolved intetrahydrofuran (100 mL). Ethyl bromopyruvate (9 g, 0.05 mol) was addedand the mixture was refluxed for 4 hours. The reaction was cooled andthe solid that formed was filtered to give 6 grams of5-methylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. Rf 0.45,2% methanol/dichloromethane; MS m/z 205 (M+H).

Synthesis of 3-Bromo-5-methyl-imidazo[1,2-a]pyridine-2-carboxylic acidethyl ester (o): N-Bromosuccinimide (0.288 g, 0.00162 mol) was added inportions to a solution of 5-methylimidazo[1,2-a]pyridine-2-carboxylicacid ethyl ester (compound n, 0.3 g, 0.001 mol) in acetonitrile (7 mL)at 0° C. The reaction was stirred at 0° C. for 15 minutes. The solventremoved then water (10 mL) and ethyl acetate (10 mL) was added. Thelayers were separated and the organic layer dried (magnesium sulfate)then removed. The crude product was chromatographed using 30% ethylacetate/hexanes to give3-Bromo-5-methyl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester asa light brown solid. Rf 0.35, 80% ethyl acetate/hexanes; MS m/z 284(M+H).

Synthesis of5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-2-carboxylicacid ethyl ester (p):3-Bromo-5-methyl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester(compound o, 0.6 g, 0.002 mol), potassium carbonate (0.6 g, 0.004 mol),triphenylphosphine (0.06 g, 0.0002 mol),3-(trifluoromethyl)phenylboronic acid (0.4 g, 0.002 mol) andbis(acetato) bis(triphenylphosphine)palladium (II) (0.08 g, 0.0001 mol)were mixed in a microwave vial. The mixture was purged with argon.Isopropyl alcohol (20 mL) and water (3 mL) was added. The mixture washeated (120° C.) by microwaved for 25 minutes. The solvent removed thenwater (10 mL) and ethyl acetate (10 mL) was added. The layers wereseparated and the organic layer dried (magnesium sulfate) then removed.The crude product was chromatographed using 50% ethyl acetate/hexanes togive 350 mg of5-methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-2-carboxylicacid ethyl ester as a white solid. Rf 0.42, 50% ethyl acetate/hexanes;MS m/z 349 (M+H).

Synthesis of5-Methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine-2-carboxylicacid (q): Potassium hydroxide (0.2 g, 0.003 mol) was added to asuspension of5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-2-carboxylicacid ethyl ester (compound p, 0.35 g, 0.0010 mol) in methanol (0.4 mL)and water (4.7 mL). Stirred at 80° C. for 1 hour. The methanol wasremoved and 6N HCl added to the residue until pH approx. 5. The whitesolid that formed was filtered to give 290 mg of5-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine-2-carboxylic acid as a white solid. Rf 0.20, 100%ethyl acetate; MS m/z 319 (M−H).

Synthesis of[5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-yl]-carbamicacid tert-butyl ester (r): 5-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridine-2-carboxylic acid (0.28 g, 0.00087 mol) wasdissolved in tert-Butyl alcohol (compound q, 6 mL, 0.06 mol) andtriethylamine (0.15 mL, 0.0010 mol). Diphenylphosphonic azide (0.23 mL,0.0010 mol) was added and was stirred at 85° C. for 6 hours. Reactionwas cooled then water was added and the solvent evaporated. Aqueouslayer was extracted with ethyl acetate. The organics were combined thendried (magnesium sulfate) and removed in vacuo. The crude product waschromatographed using 60% ethyl acetate/hexanes to give 130 mg of[5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-yl]-carbamicacid tert-butyl ester as a yellow solid. Rf 0.40, 60% ethyl acetate; MSm/z 392 (M+H).

Synthesis of5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-ylamine(s): 4 M of Hydrogen chloride in 1,4-dioxane (0.8 mL) was added to[5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-yl]-carbamicacid tert-butyl ester (compound r, 0.14 g, 0.00036 mol). The mixture wasstirred at room temperature for 2 hours. Solvent evaporated to give 0.1g as a yellow oil. Rf 0.42, 100% ethyl acetate; MS m/z 292 (M+H).

Synthesis of3,3-Dimethyl-N-[5-methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-yl]-butyramide(419):5-Methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-ylamine(compound s, 0.05 g, 0.0002 mol) was dissolved in acetonitrile (0.9 mL)and pyridine (0.03 mL, 0.0003 mol). t-butylacetyl chloride (0.028 mL,0.00020 mol) was added and the mixture was stirred at room temperaturefor 4 hours. Solvent was removed then ethyl acetate and saturated sodiumbicarbonate was added. The layers were separated and the organic layerdried (magnesium sulfate) then removed. The crude product waschromatographed using 60% ethyl acetate/hexanes to give 39 mg of3,3-Dimethyl-N-[5-methyl-3-(3-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridin-2-yl]-butyramideas a white solid. Rf 0.27, 100% ethyl acetate; MS m/z 390 (M+H).SH-SY5Y_EC50: 0.3399.

The following compounds were prepared according to the procedures ofMethod 4. The number next to each compound listed below corresponds tothe compound number in Table 4.

Following is a list of the compounds prepared by Method 4:

-   3,3-dimethyl-N-(5-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)butanamide    419-   4,4,4-trifluoro-3-methyl-N-(5-methyl-3-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-2-yl)butanamide    420

Table 4 sets forth potencies, purity, calculated molecular weights andmeasured molecular weights of representative compounds of the inventionin the SH-SY5Y native cell line in a FLIPR assay, for a selection ofcompounds. The compound numbers in Table 4 correspond to the compoundnumbers following each compound listed above in Example 4.

TABLE 4 Compound SH-SY5Y Purity Molecular Observed m/z No. EC50, μM (%)Weight (M + H) 419 +++ 98 389.4 390.4 420 ++ 98 429.4 430.4 “+”represents 10 μM > EC₅₀ > 3 μM “++” represents 3 μM > EC₅₀ > 0.5 μM“+++” represents EC₅₀ < 0.5 μM

Example 5 Preparation of3,3,3-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)propanamide(7)

Synthesis of N-(5-fluoropyridin-2-yl)-4-methylbenzenesulfonamide (1):2-Amino-5-fluoropyridine (4.0 g, 0.036 mol) was dissolved in pyridine(40 mL) and p-toluenesulfonyl chloride (7.5 g, 0.039 mol) was added. Thereaction was heated at 80° C. for 24 hours then cooled and the pyridinewas removed under vacuum. The residue was partioned between water (100mL) and ethyl acetate (100 mL). The layers were separated and theorganic layer was washed (3×100 mL) with water then dried and solventstripped to give cleanN-(5-fluoropyridin-2-yl)-4-methylbenzenesulfonamide 1 Rf 0.42, 50% E/H;MS m/z 267 (M+H).

Synthesis of 2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)acetamide (2):Sodium hydride (0.43 g, 0.018 mol) was mixed with N,N-Dimethylformamide(67.4 mL) and N-(5-fluoropyridin-2-yl)-4-methylbenzenesulfonamide 1 (4.0g, 0.015 mol) was added. The reaction was stirred at room temperaturefor 10 minutes. Iodoacetamide (3.3 g, 0.018 mol) was added and themixture was stirred at room temperature for 24 hours. The reaction waspoured into water (100 mL) and extracted with ethyl acetate (4×75 mL).Organic layers were combined then dried with magnesium sulfate and thesolvent removed. The crude product was chromatographed on silica using5% methanol in dichloromethane to give2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)acetamide 2 Rf 0.26, 5%methanol.dichloromethane; MS m/z 324 (M+H)

Synthesis of2,2,2-trifluoro-N-(6-fluoroimidazo[1,2-a]pyridin-2-yl)acetamide (3):2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)acetamide (1.5 g, 0.0046 mol)was mixed with dichloromethane (18 mL) and trifluoroacetic anhydride (10mL, 0.09 mol) was added. The reaction was stirred at room temperature 30min. The solvent was removed and residue taken up in ethyl acetate (50mL) then washed with saturated NaHCO₃ (3×50 mL). The organic layer wasdried with magnesium sulfate and the solvent removed. The residue waschromatographed on silica (70% ethyl acetate/hexanes) to give2,2,2-trifluoro-N-(6-fluoroimidazo[1,2-a]pyridin-2-yl)acetamide 3 Rf0.35, 70% ethyl acetate/hexanes; MS m/z 248 (M+H)

Synthesis of2,2,2-trifluoro-N-(6-fluoro-3-iodoimidazo[1,2-a]pyridin-2-yl)acetamide(4): 2,2,2-trifluoro-N-(6-fluoroimidazo[1,2-a]pyridin-2-yl)acetamide(0.89 g, 0.0036 mol) was dissolved in acetonitrile (20 mL) and wascooled at 0° C. N-Iodosuccinimide (0.89 g, 0.0040 mol) was added and thereaction was stirred for 30 minutes. The mixture was poured into water(100 mL) and extracted with ethyl acetate (3×100 mL). The combinedorganics were dried with magnesium sulfate and the solvent removed. Theresidue was chromatographed on silica (60% ethyl acetate/hexanes) togive2,2,2-trifluoro-N-(6-fluoro-3-iodoimidazo[1,2-a]pyridin-2-yl)acetamide 4Rf 0.40, 60% ethyl acetate/hexanes; MS m/z 374 (M+H).

Synthesis of2,2,2-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)acetamide(Q:2,2,2-trifluoro-N-(6-fluoro-3-iodoimidazo[1,2-a]pyridin-2-yl)acetamide(0.500 g, 0.00134 mol) was dissolved in tetrahydrofuran (16 mL) and wascooled at −78° C. N-Butyllithium (2 molarin cyclohexane, 1.6 mL) wasadded and the reaction was warmed to −20 for 15 minutes then chilled to−78° C. Methyl iodide (110 uL, 0.0017 mol) was added and the reactionwas allowed to warm to room temperature. The reaction was poured intoice water and extracted with ethyl acetate (3×50 mL). The combinedorganics were dried (magnesium sulfate) and solvent removed. Residuechromatographed on silica (50% ethyl acetate/hexanes) to give2,2,2-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)acetamide5 Rf 0.47, 50% ethyl acetate/hexanes; MS m/z 262 (M+H).

Synthesis of 6-fluoro-3-methylimidazo[1,2-a]pyridin-2-amine (6):2,2,2-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)acetamide(0.188 g, 0.00072 mol) was dissolved in methanol (4.0 mL) and water (0.5mL). Potassium carbonate (0.40 g, 0.0029 mol) was added and heated inthe microwave for 45 min at 100° C. The solvent concentrated and residuewas partitioned between water (50 mL) and ethyl acetate (50 mL). Thelayers were separated and the organic layer was dried (magnesiumsulfate) then chromatographed on silica (55:40:5, DCM:acetonitrle:MeOH)to give 6-fluoro-3-methylimidazo[1,2-a]pyridin-2-amine Rf 0.47,(55:40:5, DCM:acetonitrle:MeOH); MS m/z 166 (M+H).

Synthesis of3,3,3-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)propanamide(7): 6-fluoro-3-methylimidazo[1,2-a]pyridin-2-amine (0.033 g, 0.00020mol) was dissolved in dichloromethane (3.0 mL) andN,N-diisopropylethylamine (0.070 mL, 0.00040 mol) was added. Thereaction was cooled to 0° C. and 3,3,3-trifluoropropionyl chloride (29uL, 0.00024 mol) was added. The mixture was warmed to room temperatureand was stirred for 1 hour. Solvent removed and residue waschromatographed on silca (70% ethyl acetate/hexanes) to give3,3,3-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)propanamideRf 0.43, 70% ethyl acetate/hexanes; MS m/z 276 (M+H). SH-SY5Y_EC50 (μM):10.

The following compounds were prepared according to the procedures ofMethod 5. The number next to each compound listed below corresponds tothe compound number in Table 5.

-   2,2,2-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)acetamide    421-   N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    422-   N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide    423-   3,3,3-trifluoro-N-(6-fluoro-3-methylimidazo[1,2-a]pyridin-2-yl)propanamide    424-   N-(6-fluoro-3-vinylimidazo[1,2-a]pyridin-2-yl)-2-(4-fluorophenyl)acetamide    425-   2-(4-fluorophenyl)-N-(7-(trifluoromethyl)-3-vinylimidazo[1,2-a]pyridin-2-yl)acetamide    426-   3,3,3-trifluoro-N-(7-(trifluoromethyl)-3-vinylimidazo[1,2-a]pyridin-2-yl)propanamide    427-   N-(5-(benzyl(methyl)amino)imidazo[1,2-a]pyridin-2-yl)-3,3-dimethylbutanamide

Table 5 sets forth potencies, purity, calculated molecular weights andmeasured molecular weights of representative compounds of the inventionin the SH-SY5Y native cell line in a FLIPR assay, for a selection ofcompounds. The compound numbers in Table 5 correspond to the compoundnumbers following each compound listed above in Example 5.

TABLE 5 Compound SH-SY5Y Purity Molecular Observed m/z No. EC50, μM (%)Weight (M + H) 421 + 98 261.2 262.2 422 + 98 301.3 302.3 423 + 98 263.3264.3 424 + 98 275.2 276.2 425 ++ 98 313.3 314.3 426 ++ 98 363.3 364.3427 + 98 337.2 338.2 “+” represents 10 μM > EC₅₀ > 3 μM “++” represents3 μM > EC₅₀ > 0.5 μM “+++” represents EC₅₀ < 0.5 μM

Example 6 Materials and Methods

SH-SY5Y cells, a mouse neuroblastoma, rat glioma hybrid cell line,functionally express M-currents (Robbins et al., J. Physiol. 451: 159-85(1992). SH-SY5Y M-currents are likely comprised, at least in part, ofKCNQ2, KCNQ3 and KCNQ5, since these genes are reportedly robustlyexpressed in differentiated SH-SY5Y cells (Selyanko et al., J. Neurosci.19(18): 7742-56 (1999); Schroeder et al., J. Biol. Chem. 275(31):24089-95 (2000)) and KCNQ3 dominant—negative constructs reduce M-currentdensity in these cells (Selyanko et al., J. Neurosci. 22(5): RC212(2002).

SH-SY5Y were maintained in DMEM (high glucose) supplemented with 10%fetal bovine serum, 0.05 mM pyridoxine, 0.1 mM hypoxanthine, 400 nMaminopterin, 16 mM thymidine, 50 μgml⁻¹ gentamycin and 10 mM HEPES, inan incubator at 37° C. with a humidified atmosphere of 5% CO₂. Cellswere plated in 96 well plates differentiated by addition of 10 μM PGE1and 50 μM isomethylbutylxanthine to the growth media prior to study.

Differentiated SH-SY5Y cells were loaded with voltage-sensitive dye byincubation in Earls Balanced Salt Solution (EBSS) containing 5 mM DiBACfor 1 h. Following loading, drug solution containing 5 mM DiBAC wasadded to each well. Changes in fluorescence were measured every 30 s for25 min. The maximum change in fluorescence was measured and expressed asa percentage of the maximum response obtained in the presence of apositive control agent.

Example 7 In Vivo Rat Assay for Anti-Convulsant Activity

Male Wistar rats were housed 4 per cage on a regular light/dark cycle(lights on 0600-1800) for one week prior to anti-convulsant testing. Theapparatus used to induce electroshock seizure was obtained fromWalhquist Instrument Co., Salt Lake City, Utah. The shock level was setat 150 mA and the duration at 0.2 seconds. A drop of 1% proparacainesolution was placed in each eye of a rat, the electrodes were placedover the eyes, and the shock was administered. Latency to hind limbextension was measured to the nearest 0.1 second. If extension did notoccur within 6 seconds, the rat was scored as protected and a value of 6seconds was recorded.

The KCNQ opener was homogenized in either 0.5% carboxymethylcellulose inwater or 0.5% methylcellulose in water) and administered orally througha steel 18-gauge rat gavage tube in a volume of 2 mL/kg of body weight.In the single dose screening assay, latency to seizure for the vehiclegroup and the KCNQ opener group were compared using t-test. Typically adose of 10 mg/kg of the opener is used. However, openers can be run n adose-response experiment where doses of 1, 3, 10 and 30 mg/Kg are used.

In the single dose screening assay, latency to seizure for the vehicleand the 10 mg/kg groups were compared using t-test. Latencies to seizurein the dose response studies were submitted to analysis of variance andall dose groups were compared to vehicle using Dunnett's method (JMP©)ver 5.1, SAS). In all cases an effect was considered significant if p≦0.05. Tables 6 and 7 provide examples of the screening anddose-response data.

TABLE 6 Rat MES Examples activity 128 +++ 153 +++ 353 +++ 180 ++ 198 +++360 + 19 +++ 20 + 225 ++ 363 ++ 23 + 24 + 271 ++ 32 + 38 ++ 51 ++ 371 ++308 +++ 316 ++ 68 +++ 89 +++ + 2-3 animals protected ++ 4-6 animalsprotected +++ 7-8 animals protected

TABLE 7 ED50 Examples (mpk) 19 2.3 371 3.6 153 0.5 19 <1 308 1.6 89 5.8

In Vivo Rat Assay for Neuropathic Pain

A neuropathic pain condition is induced in rats using a nerve injurymodel similar to the method described by Kim and Chung (Kim, S. H. &Chung, J. M. (1992) Pain 50:355-363). Rats (Male Sprague-Dawley, CharlesRiver, Wilmington, Mass.) weighing 200-300 grams were utilized. Food andwater was available ad libitum except during testing) are anesthetizedwith halothane and the L5 spinal nerve is exposed, carefully isolated,and tightly ligated with 4.0 silk suture distal to the dorsal rootganglia. The wounds are sutured and the animals are allowed to recoverin individual cages. To test the effect of a KCNQ opener on tactileallodynia following L5 nerve ligation, Von Frey tactile withdrawalthresholds are determined. Test animals are placed in a box separated bywalls with a wire mesh floor allowing access to the plantar surface ofthe paw. Tactile testing is conducted using set of calibrated nylonfibers (Von Frey hairs), each approximately 3 cm long and sequentiallyincreasing in diameter and stiffness, mounted on handles. Beginning witha medium hair, the tip of the fiber is placed on the plantar surface ofthe rat paw and applied with a pressure to make it slightly bend. If therat responds by lifting its paw the next descending hair is tested.Failure to lift the hind paw after 4 seconds is scored as a negativeresponse and the next ascending hair is applied. Dixon's Up-Down Methodis applied for a total of 6 responses following and including the firstchange in response to determine 50% paw withdrawal thresholds. Dataanalysis was conducted using analysis of variance and appropriatepost-hoc comparisons (P<0.05) as previously described. ED₅₀ values wereestimated using least squares linear regression.

Baseline measurements of allodynia are performed immediately prior tosubject selection and compound administration. Only rats found to beallodynic (mean 50% gram withdrawal thresholds <5) are selected assubjects for each days study. Sample sizes vary with number of availableallodynic animals, generally 5-8 per treatment group. The KCNQ openerwas homogenized in either 0.5% carboxymethylcellulose in water or 0.5%methylcellulose in water) and administered orally through a steel18-gauge rat gavage tube in a volume of 2 mL/kg of body weight. Thedoses range from 1-100 mg/kg with a typical experiment using 1, 3, 10and 30 mg/kg to generate and ED₅₀ value. The openers are typically given30 minutes to 2 hours prior to testing. Additional paw withdrawalthresholds are measured at various time intervals after compoundadministration. Examples 153 and 19 were evaluated in this assay.Example 153 has an ED₅₀ value of 1.9 mg/kg and Example 19 has an ED₅₀ of10 mg/kg.

In Vivo Rat Model for Inflammatory Pain

In this model of acute inflammation, carrageenan is injected into thepaw resulting in a local inflammation and thermal hyperalgesia, which isdemonstrated by a reduction in the escape latency of the inflamed pawwhen presented with a thermal stimulus. Compounds with anti-hyperalgesicactivity will increase (or lengthen) the escape latency of the inflamedpaw.

To induce a local inflammation, 50 μL of a 1% solution of λ-carrageenanin sterile water is injected subcutaneously into the plantar surface ofthe right hind paw of the rat (Sprague Dawley rats, sample size=8 pertreatment group). The KCNQ openers typically at doses ranging from 1-100mg/kg were homogenized in either 0.5% carboxymethylcellulose in water or0.5% methylcellulose in water and administered orally through a steel18-gauge rat gavage tube in a volume of 2 mL/kg of body weight 30minutes prior to carrageenan injection. After carrageenan injectionbehavioral testing is conducted at the appropriate time following openeror vehicle administration (generally T_(max), the time of maximum plasmalevels of the compound being tested). To assess the thermally evoked pawwithdrawal response, a commercially available Hargreaves Box was used(UCSD Department of Anesthesiology, San Diego; La Jolla, Calif.,stimulus intensity 5.25 amps). Rats were placed on a thin glass surfacein individual chambers made of clear plastic. A small high intensityprojection bulb, mounted on a moveable arm under the glass with amirrored base that can be positioned under the paw, served as thethermal stimulus. The time to withdrawal response is measured in secondsand assigned as the response latency. Both right and left hind paws(inflamed and uninflamed paws) were tested in each animal and the datareported as the mean of three measurements taken within a 5 minute timeperiod. Example 153 had an ED₅₀ of 0.5-1 mg/kg.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A compound of Formula (IX):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, R¹¹and R¹² are each independently selected from the group consisting of —H,halogen, C₁₋₈haloalkyl, —CN, C₁₋₈alkyl, C₁₋₈alkoxy, aryloxy andaryl-C₁₋₈alkoxy; R¹³ is selected from the group consisting of —H,C₁₋₈alkyl, C₂₋₈alkenyl, aryl, C₃₋₈cycloalkyl, aryl-C₁₋₆alkyl,C₃₋₈cycloalkyl-C₁₋₈alkyl, heteroaryl and heteroaryl-C₁₋₆alkyl, whereinthe aromatic portion of the R¹³ group is optionally substituted withfrom 1-3 R^(a) substituents, each R^(a) is independently selected fromthe group consisting of halogen, C₁₋₈haloalkoxy, C₁₋₈alkoxy,C₁₋₈haloalkyl, —CN and R^(b), wherein R^(b) is C₁₋₈alkyl optionallysubstituted with from 1-2 substituents selected from halogen, —CN, —OH,C₁₋₈haloalkoxy or C₁₋₈alkoxy; or any two adjacent R^(a) substituentstogether with the atoms to which they are attached form a 5- or6-membered carbocyclic ring, optionally substituted with a C₁₋₈alkyl;R¹⁴ is selected from the group consisting of C₁₋₈alkyl, C₁₋₈haloalkyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₈alkyl, aryl, aryl-C₁₋₈alkyl,C₁₋₈alkoxy, aryl-C₁₋₈alkoxy, C₄₋₅heterocycloalkyl,C₄₋₅heterocycloalkyl-C₁₋₈alkyl, R^(c), —NHR^(d) and —N(R^(d))₂, whereinR^(c) is C₁₋₈alkyl substituted with from 1-2 members selected from —OH,—OC(O)C₁₋₈alkyl, —CH₂N(R^(d))₂, —OC(O)aryl, C₁₋₈alkoxy or aryloxy andR^(d) is C₁₋₈alkyl or aryl-C₁₋₈alkyl, wherein the aromatic portion ofthe R¹⁴ group is optionally substituted with from 1-3 R^(e) substituentsindependently selected from the group consisting of halogen,C₁₋₈haloalkyl, C₁₋₈alkyl, C₁₋₈alkoxy, —CN or haloalkoxy, —OH,—OC(O)O—R^(f), —OC(O)R^(f), —OC(O)NHR^(f), —OC(O)N(R^(f))₂, —S(O)R^(f),—S(O)₂R^(f), —SO₂NH₂, —S(O)₂NHR^(f), —S(O)₂N(R^(f))₂, —NHS(O)₂R^(f),—NR¹S(O)₂R^(f), —C(O)NH₂, —C(O)NHR¹, —C(O)N(R^(f))₂, —C(O)R^(f), —C(O)H,wherein each R^(f) is independently a C₁₋₈alkyl; and the cycloalkylportion of the R¹⁴ group is optionally substituted with from 1-3substituents selected from halogen, C₁₋₈alkyl or optionally fused with a5- or 6-membered aromatic ring having from 0-2 heteroatoms as ringmembers selected from N, O or S; R¹⁵ is —H or —C(O)C₁₋₈alkyl; Z¹ is ═N—or ═C(R¹⁶)— and Z² is ═N— or ═C(R¹⁷)—, wherein R¹⁶ and R¹⁷ are eachindependently —H, C₁₋₈alkyl, halogen, —CN, C₁₋₈haloalkyl,C₁₋₈haloalkoxy, —OR^(g) or —N(R^(g))₂, wherein R^(g) is independently—H, C₁₋₈alkyl or aryl-C₁₋₈alkyl, with the proviso that Z¹ and Z² are notsimultaneously ═N—; at each occurrence, “alkyl” by itself or as part ofanother substituent, is an unsubstituted, fully saturated, straight orbranched chain hydrocarbon radical; at each occurrence, “cycloalkyl” byitself or as part of another substituent is an unsubstituted, fullysaturated, cyclic hydrocarbon radical; and at each occurrence, “aryl” byitself or as part of another substituent is a monovalent monocyclic,bicyclic or polycyclic polyunsaturated aromatic hydrocarbon radical. 2.The compound of claim 1, wherein R¹⁵ is —H.
 3. The compound of claim 1,having Formula (IXa):

wherein R¹⁶ and R¹⁷ are each independently —H, C₁₋₈alkyl, halogen, —CN,C₁₋₈haloalkyl, C₁₋₈haloalkoxy, —OR^(g) or —N(R^(g))₂, wherein R^(g) isindependently —H, C₁₋₈alkyl or aryl-C₁₋₈alkyl.
 4. The compound of claim3, wherein R¹⁵ is —H.
 5. The compound of claim 1, having a Formulaselected from the group consisting of:

wherein: R¹⁶ and R¹⁷ are each independently —H, C₁₋₈alkyl, halogen, CN,C₁₋₈haloalkyl, C₁₋₈haloalkoxy, —OR^(g) or —N(R^(g))₂, wherein R^(g) isindependently —H, C₁₋₈alkyl or aryl-C₁₋₈alkyl; the subscripts m and nare each independently an integer of 0-3; R^(13a) is selected from thegroup consisting of cyclopropyl, cyclobutyl, cyclopentyl cyclohexyl and2,2-dimethylpropyl; R¹⁸ and R¹⁹ are each independently selected from thegroup consisting of halogen, C₁₋₈haloalkoxy, C₁₋₈alkoxy, C₁₋₈haloalkyl,—CN and R^(b); and R²³ and R²⁴ are each independently —H, C₁₋₈alkyl,halogen, C₁₋₈haloalkyl, —CN, —NH₂, —NHC 18alkyl, —N(C₁₋₈alkyl)₂ orR^(e).
 6. The compound of claim 5, wherein R¹⁵ is —H.
 7. The compound ofclaim 1, having Formula (IXb):


8. The compound of claim 7, having a Formula selected from:

wherein the subscripts p and q are each independently an integer of 0-3;and R²⁰ and R²¹ are each independently selected from the groupconsisting of halogen, C₁₋₈haloalkoxy, C₁₋₈alkoxy, C₁₋₈haloalkyl, —CNand R^(b).
 9. The compound of claim 1, having Formula (IXc):


10. The compound of claim 9, having the Formula:

wherein the subscript r is an integer of 0-3; and R²² is selected fromhalogen, C₁₋₈haloalkoxy, C₁₋₈alkoxy, C₁₋₈haloalkyl, —CN or R^(b). 11.The compound of claim 1, wherein R¹¹ is —H, —CH₃, —CF₃, —CN, —OCH₃, —Cl,PhO—, Ph-CH₂CH₂O— or PhCH₂O—.
 12. The compound of claim 1, wherein R¹²is —H, —F, —Cl, —Br, —CN, —CH₃, —CF₃, —OCH₃, PhO—, Ph-CH₂CH₂O— orPhCH₂O—.
 13. The compound of claim 3, wherein R¹¹ is —H, —CH₃, —CF₃,—OCH₃, —Cl, PhO— or PhCH₂O— and R¹² is —H, —F, —Cl, —Br, —CN, —CH₃,—CF₃, PhO—, PhCH₂O— or —OCH₃.
 14. The compound of claim 7, wherein R¹¹is —H and R¹² is —Cl, —CH₃ or —CF₃.
 15. The compound of claim 1, whereinR¹⁶ is selected from —H, C₁₋₈alkyl, C₁₋₈haloalkyl, C₁₋₈haloalkoxy,halogen, —OH, C₁₋₈alkoxy or aryl-C₁₋₆alkoxy.
 16. The compound of claim1, wherein R¹⁷ is selected from —H, C₁₋₈alkyl, C₁₋₈haloalkyl,C₁₋₈haloalkoxy, halogen, —OH, C₁₋₈alkoxy or aryl-C₁₋₆alkoxy.
 17. Thecompound of claim 1, wherein R¹⁶ is selected from —H, —F, —CF₃, —OCF₃,—CH₃, —N(CH₃)(CH₂Ph), —OH, C₁₋₄alkoxy or benzyloxy.
 18. The compound ofclaim 1, wherein R¹⁷ is selected from —H, —F, —CF₃, —OCF₃, —CH₃,—N(CH₃)(CH₂Ph), —OH, C₁₋₄alkoxy or benzyloxy.
 19. The compound of claim1, wherein R¹⁶ and R¹⁷ are —H.
 20. The compound of claim 1, wherein R¹³is selected from the group consisting of —H, C₁₋₈alkyl, C₂₋₈alkenyl,aryl, C₃₋₈cycloalkyl, aryl-C₁₋₆alkyl, C₃₋₈Cycloalkyl-C₁₋₈alkyl and 5- or6-membered heteroaryl having from 1-3 heteroatoms as ring membersselected from N, O or S, wherein the aryl or heteroaryl moiety of theR¹³ group is optionally substituted with from 1-3 R^(a) substituents,each R^(a) is independently selected from the group consisting ofhalogen, —OCF₃, C₁₋₈alkoxy, —CF₃, —CN, hydroxy-C₁₋₈alkyl,C₁₋₈alkoxy-C₁₋₈alkyl, C₁₋₈haloalkyl, cyano-C₁₋₈alkyl,C₁₋₈haloalkoxy-C₁₋₈alkyl; or optionally any two adjacent R^(a)substituents together with the atoms to which they are attached form a5- or 6-membered carbocyclic ring, optionally substituted with aC₁₋₈alkyl.
 21. The compound of claim 1, wherein R¹³ is selected from thegroup consisting of: i) —H, halogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₈alkyl; ii) phenyl, benzyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrizinyl, 3-pyridazinyl, 4-pyridazinyl,2-pyrimidinyl or 1,3,5-triazin-2-yl, each of which is optionallysubstituted with from 1-3 substituents independently selected from —F,Br, Cl, I, —CH₃, C₁₋₈alkyl, isopropyl, —CF₃, —CN, —C(CH₃)₂CN, —OCF₃,C₁₋₄alkoxy or —CHF₂; and iii) 2-thiazolyl, 4-thiozoly, 5-thiazolyl,2-benzothiazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, each of whichis optionally substituted with a C₁₋₈alkyl.
 22. The compound of claim 1,wherein R¹³ is selected from the group consisting of —H, Cl, Br, —I,—CH₃, vinyl, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,2,4-difluorophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl,2,6-difluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2-pyridyl,3-pyridyl, 4-pyridyl, cyclopropyl, 2,2-dimethylpropyl, 2-fluorobenzyl,3-fluorobenzyl, 4-fluorobenzyl, 3-(2-cyanopropan-2-yl)phenyl,4-(2-cyanopropan-2-yl)phenyl, 6-fluoro-3-pyridyl, 2-fluoro-3-pyridyl,4-fluoro-3-pyridyl, 5-fluoro-3-pyridyl, 6-cyano-3-pyridyl,2-cyano-3-pyridyl, 4-cyano-3-pyridyl, 5-cyano-3-pyridyl, 2-cyanophenyl,3-cyanophenyl, 4-cyanophenyl, 6-fluoro-2-pyridyl, 3-fluoro-2-pyridyl,4-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-trifluoromethyl-2-pyridyl,3-trifluoromethyl-2-pyridyl, 4-trifluoromethyl-2-pyridyl,5-trifluoromethyl-2-pyridyl, 3-difluoromethyl-4-fluorophenyl,3-difluoromethyl-5-fluorophenyl, 3-fluoro-4-difluoromethylphenyl,3-fluoro-4-trifluoromethoxyphenyl, 3-fluoro-5-trifluoromethoxyphenyl,3-fluoro-4-cyanophenyl, 3-fluoro-5-cyanoyphenyl,3-fluoro-4-trifluoromethylphenyl, 3-fluoro-5-trifluoromethylphenyl,3-trifluoromethyl-4-fluorophenyl, 3-trifluoromethyl-4-methoxyphenyl,3-trifluoromethyl-5-methoxyphenyl, 3-methoxy-4-trifluoromethylphenyl,3-fluoro-4-methylphenyl, 3-fluoro-5-methylphenyl,3-methyl-4-fluorophenyl, 4-trifluoromethyl-3-pyridyl,5-trifluoromethyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl,5-methyl-2-pyridyl, 3-methyl-2-pyridyl, 4-methyl-2-pyridyl,6-methyl-2-pyridyl, benzothiazol-2-yl, 3,4-difluorophenyl,3-5-difluorophenyl, 2-pyrimidinyl, 3-methyl-4-fluorophenyl,3-methyl-5-fluorophenyl, 3-fluoro-4-methylphenyl,3,5-difluoro-4-methylphenyl, 3-methyl-4-chlorophenyl,3-methyl-5-chlorophenyl, 3-chloro-4-methylphenyl, 3-chloro-2-pyridyl,4-chloro-2-pyridyl, 5-chloro-2-pyridyl, 6-chloro-2-pyridyl,3-methoxy-2-pyridyl, 4-methoxy-2-pyridyl, 5-methoxy-2-pyridyl,6-methoxy-2-pyridyl, 1-isopropyl-4-pyrazolyl, cyclohexylmethyl,cyclohexyl, 3-methyl-1-butyl, cyclopentyl, 2-thiazolyl, 4-thiazolyl,5-thiazolyl, 2-methyl-4-thiazolyl, 5-methyl-2-thiazolyl and4-methyl-2-thiazolyl.
 23. The compound of claim 7, wherein R¹³ is2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl,2-trifluoromethoxyphenyl, 2-trifluoromethoxyphenyl, 2,2-dimethylpropyl,cyclopropylmethyl, cyclopropyl, 2-thiazolyl, benzothiazol-2-yl,6-trifluoromethyl-2-pyridyl, 3-trifluoromethyl-2-pyridyl,4-trifluoromethyl-2-pyridyl or 5-trifluoromethyl-2-pyridyl.
 24. Thecompound of claim 9, wherein R¹³ is 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl,2-trifluoromethoxyphenyl, 3-trifluoromethoxyphenyl,4-trifluoromethoxyphenyl, 2-chlorophenyl, 3-chlorophenyl or4-chlorophenyl.
 25. The compound of claim 1, wherein R¹³ is C₁₋₈alkyl,C₃₋₈cycloalkyl or C₃₋₈cycloalkyl-C₁₋₄alkyl.
 26. The compound of claim25, wherein R¹³ is selected from the group consisting of 2-methylbutyl,2,2-dimethylpropyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, t-butyl and isobutyl.
 27. The compound of claim1, wherein R¹⁴ is selected from the group consisting of C₁₋₈alkyl,C₁₋₈haloalkyl, C₃₋₈cycloalkyl, C₃₋₈cycloalkyl-C₁₋₈alkyl, aryl-C₁₋₈alkyl,C₁₋₈alkoxy, aryl-C₁₋₈alkoxy, C₄₋₅heterocycloalkyl,C₄₋₅heterocycloalkyl-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl,C₁₋₈alkyl-C(O)O—C₁₋₈alkyl, aryl-C(O)O—C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl oraryloxy-C₁₋₈alkyl, —NHR^(d) and —N(R^(d))₂, wherein R^(d) is C₁₋₈alkylor aryl-C₁₋₈alkyl; wherein the aromatic portion of the R¹⁴ group isoptionally substituted with from 1-3 substituents selected from thegroup consisting of halogen, C₁₋₈haloalkyl, C₁₋₈alkyl, C₁₋₈alkoxy, —CNor haloalkoxy and the cycloalkyl portion of the R¹⁴ group is optionallysubstituted with from 1-3 substituents selected from halogen, C₁₋₈alkylor optionally fused with a 5- or 6-membered aromatic ring having from0-2 heteroatoms as ring members selected from N, O or S.
 28. Thecompound of claim 1, wherein R¹⁴ is selected from the group consistingof C₁₋₈alkyl, C₁₋₈haloalkyl, C₁₋₈alkoxy, C₄₋₅heterocycloalkyl,C₄₋₅heterocycloalkyl-C₁₋₈alkyl, hydroxyl-C₁₋₈alkyl,C₁₋₈alkyl-C(O)O—C₁₋₈alkyl, C₁₋₈alkoxy-C₁₋₈alkyl, —NH(C₁₋₈alkyl) and—N(C₁₋₈alkyl)₂, phenyl, phenyl-C₁₋₈alkyl, phenyl-C₁₋₈alkoxy,phenyl-C(O)O—C₁₋₈alkyl, phenoxy-C₁₋₈alkyl or (phenyl-C₁₋₈alkyl)NH—,C₃₋₈cycloalkyl and C₃₋₈cycloalkyl-C₁₋₈alkyl, wherein each phenyl moietyis optionally substituted with from 1-3 members independently selectedfrom halogen, —CF₃, —CN, —C₁₋₈alkyl or —C₁₋₈alkoxy; and each cycloalkylmoiety is optionally substituted with 1-2 substituents selected fromhalogen and C₁₋₈alkyl or optionally fused with a phenyl ring.
 29. Thecompound of claim 28, wherein R¹⁴ is selected from the group consistingof —CH₃, —CF₃, 4-fluorophenyl, 3,4-difluorophenyl, benzyl,2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,2-dimethylpropyl,2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclopentylmethyl,Ph(CH₃)CH₂—, cyclopropylmethyl, cyclohexylmethyl, 2-methoxybenzyl,3-methoxybenzyl, 4-methoxybenzyl, PhCH₂CH₂—, 2-trifluoromethylbenzyl,3-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 2-cyanobenzyl,3-cyanobenzyl, 4-cyanobenzyl, 3,4-difluorobenzyl, 3,5-difluorobenzyl,3,6-difluorobenzyl, 2,6-difluorobenzyl, 2,4,4-trimethylpentyl,2-fluoro-6-chloro-benzyl, 2-fluoro-3-chloro-benzyl,2-fluoro-4-chloro-benzyl, 2-fluoro-5-chloro-benzyl,3-fluoro-4-chlorobenzyl, 3-fluoro-5-chlorobenzyl,3-fluoro-6-chlorobenzyl, 3,4-dichlorobenzyl, 3,5-dichlorobenzyl,3,6-dichlorobenzyl, 2,6-dichlorobenzyl, 2-methylbenzyl, 3-methylbenzyl,4-methylbenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl,2-methyl-3,3,3-trifluoropropyl, benzyloxy, 2-methylbutyl, CN—CH₂CH₂CH₂—,(CH₃)₂CHCH(CH₃)—, 3,3-dimethylbutyl, cyclopropylethyl,4,4,4-trifluorobutyl, (bicyclo[2.2.1]heptan-2-yl)methyl,(1-methylcyclohexyl)methyl, (1-methylcyclopentyl)methyl, (CH₃)₃CCH(OH)—,cyclobutylmethyl, CH₃C(O)OCH₂C(CH₃)₂CH₂—, (OH)CH₂C(CH₃)₂CH₂—,1,1-difluoro-2,2-dimethylpropyl, t-butoxymethyl, t-butoxyethyl,2-(4-fluorophenyl)ethylamino, 4-fluorobenzylamino, t-butylamino,2-cyano-2-methylpropyl, cyclopentylethyl, Ph-O—CH₂—, Ph-O—CH(CH₃)—,4-phenoxybenzyl, PhCH₂OCH₂—, 2-tetrahydropyranyl,3,4-dichlorophenoxymethyl, 3,5-dichlorophenoxymethyl,3,6-dichlorophenoxymethyl, 2,3-dichlorophenoxymethyl,2,4-dichlorophenoxymethyl, 2,5-dichlorophenoxymethyl,2,6-dichlorophenoxymethyl, 2-fluorophenoxyethyl, 3-fluorophenoxyethyl,4-fluorophenoxyethyl, (tetrahydropyran-4-yl)methyl, 3,3-dimethylbutyl,2-trifluoromethoxybenzyl, 3-trifluoromethoxybenzyl,4-trifluoromethoxybenzyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclooctyl, cycloheptyl, 2-indanyl, 1-indanyl, isobutyl,3,3-difluorocyclopentylmethyl, 4,4-difluorocyclohexyl,2,2-difluorocyclopropyl, (R)—CF₃CH(CH₃)CH₂—, (S)—CF₃CH(CH₃)CH₂—,CH₃C(O)OCH(t-butyl)-, HOCH(t-butyl)-, 2-tetrahydrofuranyl,

wherein the wavy line indicates the point of attachment to the rest ofthe molecule.
 30. The compound of claim 1, wherein R¹⁴ is selected fromthe group consisting of 3,4-difluorobenzyl, cyclobutyl, —CH(s-OH)-t-Bu,—CH₂-t-Bu, —CH₂CH(CF₃)CH₃, (R)—CH₂CH(CF₃)CH₃, (S)—CH₂CH(CF₃)CH₃,—CH₂CH(CF₃)CH₃, cyclohexylmethyl, —CH(CH₃)CH(CH₃)₂, 4-fluorobenzyl,3-fluorobenzyl, cyclobutylmethyl, —CH₂CH₂-t-Bu, 4-fluorophenyl,3,4-difluorophenyl, —CH(CH₃)-t-Bu, (R)-2-tetrahydrofuranyl,—CH₂CH(CH₃)CF₃, cyclopentyl, —CH₂CH₂CF₃, 3,3-difluorocyclopentylmethyl,4,4-difluorocyclohexyl and 2,2-difluorocyclopropyl.
 31. The compound ofclaim 1, wherein R¹¹, R¹⁶ and R¹⁷ are —H.
 32. The compound of claim 7,wherein R¹¹ and R¹⁶ are —H.
 33. The compound of claim 9, wherein R¹¹ andR¹⁷ are —H.
 34. A pharmaceutical composition comprising a compound ofclaim 1 and a pharmaceutically acceptable excipient.
 35. A method ofmodulating activity of a potassium ion channel in a subject, said methodcomprising: administering to said subject in need thereof an effectiveamount of a compound of claim 1 to modulate the activity of a potassiumchannel.
 36. A method of increasing ion flow through voltage dependentpotassium channels in a cell, said method comprising: contacting thecell with a compound of claim 1 in an amount sufficient to modulate thepotassium ion channels.
 37. A method of treating, preventing, inhibitingor ameliorating a central or peripheral nervous system disorder orcondition through modulation of a potassium ion channel, said methodcomprising: administering to a subject in need of such treatment aneffective amount of a compound of claim
 1. 38. The method of claim 37,wherein said disorder or condition is selected from the group consistingof migraine, ataxia, Parkinson's disease, bipolar disorders, trigeminalneuralgia, spasticity, mood disorders, brain tumors, psychoticdisorders, myokymia, seizures, epilepsy, stroke, hearing and visionloss, Alzheimer's disease, age-related memory loss, learningdeficiencies, retinal degeneration, pain anxiety, neuronal degeneration,motor neuron diseases and urinary incontinence.
 39. The method of claim38, wherein said condition or disorder is selected from epilepsy,seizure, retinal degeneration, pain, anxiety, neuronal degeneration,hearing loss or bipolar disorder.
 40. The method according to claim 39,wherein said pain is a member selected from neuropathic pain, diabeticpain, somatic pain, cutaneous pain, visceral pain, inflammatory pain,cancer pain, migraine pain, or musculoskeletal pain.
 41. The method inaccordance with claim 39, wherein said condition or disorder is epilepsyor seizures.
 42. The method in accordance with claim 39, wherein saidcondition or disorder is hearing loss.
 43. The method in accordance withclaim 39, wherein said condition or disorder is pain or anxiety.
 44. Themethod in accordance with claim 39, wherein said condition or disorderis neuronal degeneration.
 45. The method in accordance with claim 39,wherein said condition or disorder is retinal degeneration.